Entry - *192240 - VASCULAR ENDOTHELIAL GROWTH FACTOR A; VEGFA

Vascular endothelial growth factor is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo (summary by Leung et al., 1989).

▼ Cloning and Expression

Ferrara and Henzel (1989) purified Vegf from bovine pituitary follicular cells. By SDS-PAGE, the protein had an apparent molecular mass of about 45 kD under nonreducing conditions and about 23 kD under reducing conditions, suggesting the formation of homodimers.

By screening a human leukemia cell line cDNA library with bovine Vegf as probe, Leung et al. (1989) cloned VEGF. The deduced protein has a 26-amino acid signal peptide at its N terminus, and the mature protein contains 165 amino acids. Leung et al. (1989) also identified clones encoding VEGF species with 121 amino acids and 189 amino acids, which result from a 44-amino acid deletion at position 116 and a 24-amino acid insertion at position 116, respectively. VEGF shares homology with the PDGF A chain (PDGFA; 173430) and B chain (PDGFB; 190040), including conservation of all 8 cysteines found in PDGFA and PDGFB. However, VEGF has 8 additional cysteines within its C-terminal 50 amino acids.

Tischer et al. (1991) demonstrated that VEGF, also called vascular permeability factor (VPF), is produced by cultured vascular smooth muscle cells. By analysis of transcripts from these cells by PCR and cDNA cloning, they demonstrated 3 different forms of the VEGF coding region, resulting in predicted products of 189, 165, and 121 amino acids.

By RT-PCR on carcinoma cell lines, Poltorak et al. (1997) identified a VEGF isoform predicted to contain 145 amino acids and to lack exon 7, which they termed VEGF145.

▼ Gene Structure

Tischer et al. (1991) found that the VEGF gene contains 8 exons. The various VEGF coding region forms arise through alternative splicing: the 165-amino acid form is missing the residues encoded by exon 6, whereas the 121-amino acid form is missing the residues encoded by exons 6 and 7.

▼ Gene Function

Ferrara and Henzel (1989) determined that purified bovine Vegf was mitogenic to adrenal cortex-derived capillary endothelial cells and to several other vascular endothelial cells, but it was not mitogenic toward nonendothelial cells.

Leung et al. (1989) demonstrated that culture media conditioned by human embryonic kidney cells expressing either bovine or human VEGF cDNA promoted proliferation of capillary endothelial cells.

The homodimeric protein VEGF is the only mitogen that specifically acts on endothelial cells. It may be a major regulator of tumor angiogenesis in vivo. Millauer et al. (1994) observed in mouse that its expression was upregulated by hypoxia and that its cell surface receptor, Flk1 (KDR; 191306), is exclusively expressed in endothelial cells. Folkman (1995) noted the importance of VEGF and its receptor system in tumor growth and suggested that intervention in this system may provide promising approaches to cancer therapy.

Mattei et al. (1996) noted that VEGF and placental growth factor (601121) constitute a family of regulatory peptides capable of controlling blood vessel formation and permeability by interacting with 2 endothelial tyrosine kinase receptors, FLT1 (165070) and KDR/FLK1. They stated that a third member of this family may be the ligand of the related FLT4 receptor (136352), which is involved in lymphatic vessel development.

Dantz et al. (2002) showed that VEGF is a candidate hormone for facilitating glucose passage across the blood-brain barrier under critical conditions. In 16 healthy men, VEGF serum concentrations increased under 6 hours of insulin-induced hypoglycemic conditions from 86.1 +/- 13.4 to 211.6 +/- 40.8 pg/ml (P equal to 0.002), whereas in the hyperinsulinemic euglycemic control condition, no change was observed. During hypoglycemia, serum VEGF, but no other counterregulatory hormone, was associated with preserved neurocognitive function, as measured with a memory test and the Stroop interference task. The authors concluded that acute hypoglycemia is accompanied by a brisk increase in circulating VEGF concentration, and that VEGF can mediate rapid adaptation of the brain to neuroglycopenia.

Poltorak et al. (1997) demonstrated by immunoblot analysis that VEGF145 is secreted as an approximately 41-kD homodimer. Injection of VEGF145 into mouse skin induced angiogenesis. VEGF145 inhibited binding by VEGF165 to the KDR/FLK1 receptor in cultured endothelial cells. Like VEGF189, but unlike VEGF165, VEGF145 binds efficiently to the extracellular matrix (ECM) by a mechanism that is not dependent on ECM-associated heparan sulfates.

Soker et al. (1998) described the purification and the expression cloning from tumor cells of a VEGF receptor that binds VEGF165 but not VEGF121. This isoform-specific VEGF receptor (VEGF165R) is identical to human neuropilin-1 (602069), a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance. When coexpressed in cells with KDR, neuropilin-1 enhances the binding of VEGF165 to KDR and VEGF165-mediated chemotaxis. Conversely, inhibition of VEGF165 binding to neuropilin-1 inhibits its binding to KDR and its mitogenic activity for endothelial cells. Soker et al. (1998) proposed that neuropilin-1 is a VEGF receptor that modulates VEGF binding to KDR and subsequent bioactivity and therefore may regulate VEGF-induced angiogenesis.

To explore the possibility that VEGF and angiopoietins (see ANG2, 601922) collaborate during tumor angiogenesis, Holash et al. (1999) analyzed several different murine and human tumor models. Holash et al. (1999) noted that angiopoietin-1 (ANG1; 601667) was antiapoptotic for cultured endothelial cells and expression of its antagonist angiopoietin-2 was induced in the endothelium of co-opted tumor vessels before their regression. In contrast, marked induction of VEGF expression occurred much later in tumor progression, in the hypoxic periphery of tumor cells surrounding the few remaining internal vessels, as well as adjacent to the robust plexus of vessels at the tumor margin. Expression of Ang2 in the few surviving internal vessels and in the angiogenic vessels at the tumor margin suggested that the destabilizing action of angiopoietin-2 facilitates the angiogenic action of VEGF at the tumor rim. Holash et al. (1999) implanted rat RBA mammary adenocarcinoma cells into rat brains. Tumor cells rapidly associated with and migrated along cerebral blood vessels. There was minimal upregulation of VEGF. Holash et al. (1999) suggested that a subset of tumors rapidly co-opts existing host vessels to form an initially well vascularized tumor mass. Perhaps as part of a host defense mechanism there is widespread regression of these initially co-opted vessels, leading to a secondarily avascular tumor and a massive tumor cell loss. However, the remaining tumor is ultimately rescued by robust angiogenesis at the tumor margin.

Funatsu et al. (2002) investigated the relationship between diabetic macular edema and the levels of VEGF and interleukin-6 (IL6; 147620) in aqueous humor and plasma. They found that aqueous levels of VEGF and IL6 correlated significantly with the severity of macular edema and that aqueous levels were significantly higher than plasma levels. In addition, the aqueous level of VEGF correlated significantly with that of IL6. The authors concluded that both VEGF and IL6 are produced together in the intraocular tissues and that both are involved in the pathogenesis of diabetic macular edema.

Watanabe et al. (2005) investigated the involvement of VEGF and ANG2 in the angiogenesis of proliferative diabetic retinopathy (PDR; see 603933). The vitreous level of ANG2 and VEGF were significantly higher in patients with PDR than in controls, and both ANG2 and VEGR levels in eyes with active PDR were significantly higher than in those with inactive PDR. The vitreous concentration of ANG2 correlated significantly with that of VEGF, suggesting an association of ANG2 and VEGF with angiogenic activity in PDR.

Helmlinger et al. (2000) showed that VEGF can stimulate the elongation, network formation, and branching of nonproliferating endothelial cells in culture that are deprived of oxygen and nutrients. As endothelial cells in tumors are exposed to chronic or intermittent hypoxic conditions, Helmlinger et al. (2000) proposed that autocrine endothelial VEGF contributes to the formation of blood vessels in a tumor and promotes its survival. When human umbilical vein endothelial cells and bovine adrenal cortex capillary endothelial cells were cultured in a sandwich system, in which the medium can only reach the cells from the edges of the culture, expression of VEGF protein increased starting from the edge of the sandwich culture and peaked in the central oxygen/nutrient-poor region. Pronounced gradients of partial pressure of oxygen (pO2) were created after 1 hour's culture, with cells on the interior experiencing oxygen levels below 30 mm Hg, dropping to about 5 mm Hg after 1.5 hours. The oxygen gradient induced a gradient of VEGF expression in the opposite direction. By 1.5 hours, there was only a moderate increase in VEGF expression apparent in the interior, with no evidence of endothelial networks. VEGF gradients were clearly established at 3 hours, while networks were only partially formed. Networks then progressed to full formation over the next 6 hours under minimal pO2. When Helmlinger et al. (2000) added anti-VEGF neutralizing antibody to sandwich cultures before positioning the upper slide, no networks were detected after 9 to 10 hours, suggesting that network formation was VEGF-dependent.

Ishida et al. (2003) studied the differential potency of 2 major VEGF isoforms, VEGF120 and VEGF164, for inducing leukocyte stasis (leukostasis) within the retinal vasculature and blood-retinal barrier (BRB) breakdown in rats. On an equimolar basis, VEGF164 was at least twice as potent as VEGF120 at inducing ICAM1 (147840)-mediated retinal leukostasis and BRB breakdown in vivo. An anti-VEGF164 aptamer inhibited both diabetic retinal leukostasis and BRB breakdown in early and established diabetes, indicating that VEGF164 is in important isoform in the pathogenesis of early diabetic macular edema.

Simo et al. (2002) found that both free IGF1 (147440) and VEGF were increased with the vitreous fluid of diabetic patients with proliferative diabetic retinopathy. The elevation of IGF1 was unrelated to the elevation of VEGF in these patients. The authors felt that their results supported the concept that VEGF was directly involved in the pathogenesis of proliferative diabetic retinopathy, whereas the precise role of free IGF1 remained to be established.

VEGF mediates angiogenic activity in a variety of estrogen target tissues. To determine whether estrogen has a direct transcriptional effect on VEGF gene expression, Mueller et al. (2000) developed a model system by transiently transfecting human VEGF promoter-luciferase reporter constructs into primary human endometrial cells and into cells derived from a well-differentiated human endometrial adenocarcinoma. These studies demonstrated that estradiol (E2)-regulated VEGF gene transcription requires a variant estrogen response element (ERE) located 1.5 kb upstream from the transcriptional start site. Site-directed mutagenesis of this ERE abrogated E2-induced VEGF gene expression.

Wulff et al. (2000) studied the localization of angiopoietin-1, angiopoietin-2, their common receptor TEK (600221), and VEGF mRNA at the different stages of the functional luteal phase and after rescue by chorionic gonadotropin (see 118860). VEGF mRNA was found exclusively in granulosa luteal cells, and the area of expression was highest in corpora lutea during simulated pregnancy. They concluded that their results were consistent with the hypothesis that VEGF and the angiopoietins play a major role in human corpus luteum regulation by paracrine actions and imply that angiopoietins are involved during the initial angiogenic phase and in luteal rescue.

Basu et al. (2001) reported that at nontoxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VEGF. Dopamine acted through D2 dopamine receptors (126450) to induce endocytosis of VEGFR2 (KDR; 191306), which is critical for promoting angiogenesis, thereby preventing VEGF binding, receptor phosphorylation, and subsequent signaling steps. The action of dopamine was specific for VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. Basu et al. (2001) concluded that their results reveal a link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors might have value in anti-angiogenesis therapy.

In the course of studies designed to assess the ability of constitutive VEGF to block tumor regression in an inducible RAS melanoma model, Wong et al. (2001) found that mice implanted with VEGF-expressing tumors sustained high mortality and morbidity that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome characterized by massive sinusoidal dilation and endothelial cell proliferation and apoptosis. Systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-induced liver pathology and prolonged survival were achieved by surgical excision of VEGF-secreting tumor or by systemic administration of a potent VEGF antagonist, thus defining a paraneoplastic syndrome caused by excessive VEGF activity. Moreover, this VEGF-induced syndrome resembles peliosis hepatis, a rare human condition that is encountered in the setting of advanced malignancies, high-dose androgen therapy, and Bartonella henselae infection. Anti-VEGF therapy may be useful in the treatment of peliosis hepatis associated with excessive tumor burden or the underlying malignancy.

VEGF is a potent stimulator of endothelial cell proliferation that has been implicated in tumor growth of thyroid carcinomas. Using the VEGF immunohistochemistry staining score, Klein et al. (2001) correlated the level of VEGF expression with the metastatic spread of 19 cases of thyroid papillary carcinoma (see 188550). The mean score +/- standard deviation was 5.74 +/- 2.59 for all carcinomas. The mean score for metastatic papillary carcinoma was 8.25 +/- 1.13 vs 3.91 +/- 1.5 for nonmetastatic papillary cancers (P less than .001). By discriminant analysis, they found a threshold value of 6.0, with a sensitivity of 100% and a specificity of 87.5%. The authors concluded that VEGF immunostaining score is a helpful marker for metastasis spread in differentiated thyroid cancers. They proposed that a value of 6 or more should be considered as high risk for metastasis threat, prompting the physician to institute a tight follow-up of the patient.

Gerber et al. (2002) described a regulatory loop by which VEGF controls survival of hematopoietic stem cells. They observed a reduction in survival, colony formation, and in vivo repopulation rates of hematopoietic stem cells after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor tyrosine kinase dramatically reduced colony formation of hematopoietic stem cells, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering soluble VEGFR1 (FLT1; 165070), which acts extracellularly, induced only minor effects. Gerber et al. (2002) concluded that their findings support the involvement in hematopoietic stem cell survival of a VEGF-dependent internal autocrine loop mechanism. Not only ligands selective for VEGF and VEGFR2 (KDR; 191306) but also VEGFR1 agonists rescued survival and repopulation of VEGF-deficient hematopoietic stem cells, revealing a function for VEGFR1 signaling during hematopoiesis.

VEGF has neurotrophic and neuroprotective effects. Because VEGF promotes the proliferation of vascular endothelial cells, Jin et al. (2002) examined the possibility that it also stimulates the proliferation of neuronal precursors in murine cerebral cortical cultures and in adult rat brain. Intracerebroventricular administration of VEGF into rat brain increased 5-bromo-2-prime-deoxyuridine labeling of cells in the subventricular zone and the subgranular zone of the hippocampal dentate gyrus, where VEGFR2 was colocalized with the immature neuronal marker doublecortin (DCX; 300121). The increase in labeling after the administration of VEGF was caused by an increase in cell proliferation, rather than a decrease in cell death, because VEGF did not reduce caspase-3 (600636) cleavage in the 2 zones mentioned. Cells labeled after VEGF treatment in vivo included immature and mature neurons, astroglia, and endothelial cells. These findings implicated VEGF in neurogenesis as well.

Geva et al. (2002) investigated VEGFA, ANGPT1 (601667), and ANGPT2 (601922) transcript profiles, and the protein products that they encode, in placentas from normotensive pregnancies throughout pregnancy. Quantitative real-time PCR analysis demonstrated that VEGFA and ANGPT1 mRNA increased in a linear pattern by 2.5% (not significant) and 2.8%/week (P = 0.034), respectively, whereas ANGPT2 decreased logarithmically by 3.5%/week (P = 0.0003). ANGPT2 mRNA was 400- and 100-fold higher than that of ANGPT1 and VEGFA, respectively, in the first trimester and declined to 20-fold and 7-fold in the third. In situ hybridization and immunohistochemical studies revealed that VEGFA was localized in cyto- and syncytiotrophoblast and perivascular cells, whereas ANGPT1 and ANGPT2 were only in syncytiotrophoblast and perivascular cells in the immature intermediate villi during the first and second trimesters, and mature intermediate and terminal villi during the third trimester. The authors concluded that these molecules may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner.

To explore the role of sinusoidal endothelial cells in the adult liver, LeCouter et al. (2003) studied the effects of VEGF receptor activation on mouse hepatocyte growth. Delivery of VEGFA increased liver mass in mice but did not stimulate growth of hepatocytes in vitro unless liver sinusoidal endothelial cells were also present in the culture. Hepatocyte growth factor (HGF; 142409) was identified as one of the liver sinusoidal endothelial cell-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGFR1 stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin.

TIMP3 (188826) encodes a potent angiogenesis inhibitor and is mutated in Sorsby fundus dystrophy (136900), a macular degenerative disease with submacular choroidal neovascularization. Qi et al. (2003) demonstrated the ability of TIMP3 to inhibit VEGF-mediated angiogenesis and identified the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGFR2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for TIMP3.

Bainbridge et al. (2003) identified a 7-amino acid peptide, RKRKKSR, encoded by VEGF exon 6, that inhibited VEGF receptor binding and angiogenesis in vitro. In a mouse model of ischemic retinal neovascularization, administration of the peptide caused a 50% inhibition of retinal neovascularization and was effective at inhibiting ischemic angiogenesis.

In vivo, Ogata et al. (2002) found that lower vitreous levels of PEDF (SERPINF1; 172860) and higher levels of vascular endothelial growth factor might be related to the angiogenesis in proliferative diabetic retinopathy.

Inactivation of the tumor suppressor gene PTEN (601728) and overexpression of VEGF are 2 of the most common events observed in high-grade malignant gliomas (see 137800). Gomez-Manzano et al. (2003) showed that transfer of PTEN to glioma cells under normoxic conditions decreased the level of secreted VEGF protein by 42 to 70% at the transcriptional level. Assays suggested that PTEN acts on VEGF most likely via downregulation of the transcription factor HIF1-alpha (603348) and by inhibition of PI3K (601232). Increased PTEN expression also inhibited the growth and migration of glioma-activated endothelial cells in culture.

Autiero et al. (2003) reported that placental growth factor (PGF; 601121) regulates inter- and intramolecular cross-talk between the VEGF receptor tyrosine kinases FLT1 (165070) and FLK1 (191306). Activation of FLT1 by PGF resulted in intermolecular transphosphorylation of FLK1, thereby amplifying VEGF-driven angiogenesis through FLK1. Even though VEGF and PGF both bind FLT1, PGF uniquely stimulated the phosphorylation of specific FLT1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross-talk through formation of FLK1/FLT1 heterodimers. Autiero et al. (2003) concluded that the inter- and intramolecular VEGF receptor cross-talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.

In preeclamptic women, Maynard et al. (2003) found increased soluble FLT1 (sFLT1) associated with decreased circulating levels of free VEGF and PGF, resulting in endothelial dysfunction in vitro that was rescued by exogenous VEGF and PGF. Administration of sFLT1 to pregnant rats induced hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. Maynard et al. (2003) suggested that excess circulating sFLT1 contributes to the pathogenesis of preeclampsia.

Alavi et al. (2003) showed that FGFB and VEGF differentially activate Raf1 (164760), resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. FGFB activated Raf1 via p21-activated protein kinase-1 (PAK1; 602590) phosphorylation of serines 338 and 339, resulting in Raf1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase-1 (MEK1; 176872). In contrast, VEGF activated Raf1 via Src kinase (CSK; 124095), leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. Alavi et al. (2003) concluded that RAF1 may be a pivotal regulator of endothelial cell survival during angiogenesis.

VEGF is a key growth factor during vascular development and one of its receptors, KDR, plays a pivotal role in endothelial cell proliferation and differentiation. Gogat et al. (2004) analyzed VEGF and KDR gene expression in the ocular structures of 7-week-old embryos and 10- and 18-week-old fetuses. Their results demonstrated that the levels of VEGF and KDR transcripts were correlated during the normal development of the ocular vasculature in humans. The complementarity between the patterns of VEGF and KDR during the early stages of development suggested that VEGF-KDR interactions played a major role in the formation and regression of the hyaloid vascular system and in the development of the choriocapillaris. In later stages (i.e., 18-week-old fetuses), the expression of KDR seemed to be linked to the development of the retinal vascular system. VEGF and KDR transcripts were unexpectedly detected in some nonvascular tissues, i.e., in the cornea and in the retina before the development of the retinal vascular system. Gogat et al. (2004) concluded that VEGF might also be necessary for nonvascular retinal developmental functions, especially for the coordination of neural retinal development and the preliminary steps of the establishment of the definitive stable retinal vasculature.

Neurogenesis occurs throughout life in mammals, including man. The most active regions for neurogenesis in the adult mammalian brain include the subventricular zone and the subgranular zone (SGZ) of the hippocampus. Neurogenesis in the SGZ is highly responsive to enriched environments, exercise, and hippocampus-dependent learning tasks. These data suggest that neurogenesis is directly coupled to experiences and stimuli that drive local neuronal activity analogous to the situation in muscle tissue. Intensive muscular activity drives myogenesis and improves muscular size and strength; similarly, robust hippocampal activity may drive neurogenesis and increase hippocampal size and cognitive strength. Cao et al. (2004) showed that hippocampal expression of VEGF is increased by both an enriched environment and performance in a spatial maze in rat. Hippocampal gene transfer of VEGF in adult rats resulted in approximately 2 times more neurogenesis associated with improved cognition. In contrast, overexpression of PGF, which signals through FLT1 but not KDR, had negative effects on neurogenesis and inhibited learning, although it similarly increased endothelial cell proliferation. Expression of a dominant-negative mutant KDR inhibited basal neurogenesis and impaired learning. Coexpression of mutant KDR antagonized VEGF-enhanced neurogenesis and learning without inhibiting endothelial cell proliferation. Furthermore, inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis. These data supported a model in which VEGF, acting through KDR, mediates the effect of the environment on neurogenesis and cognition.

Using the 3-prime UTR of rat Vegf to probe a human colon carcinoma cell line cDNA expression library, Onesto et al. (2004) identified PAIP2 (605604) as a putative regulator of VEGF expression. They demonstrated that PAIP2 stabilized VEGF mRNA, leading to increased VEGF expression. By in vitro protein-protein interactions and coimmunoprecipitation experiments, Onesto et al. (2004) showed that PAIP2 interacted with another VEGF mRNA-binding protein, HuR (ELAVL1; 603466), suggesting that PAIP2 and ELAVL1 cooperate to stabilize VEGF mRNA.

By overexpression in human and murine endothelial cells, Smith et al. (2003) determined that DDAH2 (604744) reduced the secretion of its substrate, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (see 163729). In addition, overexpression of DDAH2 increased VEGF mRNA expression and enhanced tube formation by cells grown in a 3-dimensional medium. Conversely, a DDAH inhibitor reduced tube formation in human umbilical vein endothelial cells.

Yao and Duh (2004) demonstrated that DSCR1 (RCAN1; 602917) was induced in human endothelial cells in response to VEGF, TNFA (191160), and calcium mobilization, and this upregulation was inhibited by inhibitors of the calcineurin (see 114105)-NFAT (see 600490) signaling pathway, as well as by PKC (see 176960) inhibition and a calcium chelator. Yao and Duh (2004) hypothesized that upregulation of DSCR1 in endothelial cells may act as an endogenous feedback inhibitor of angiogenesis by regulating the calcineurin-NFAT signaling pathway.

Poulaki et al. (2003) investigated the regulation of VEGF production by the thyroid carcinoma cell line SW579. They found that IGF1 (147440) upregulated VEGF mRNA expression and protein secretion. Transfection of SW579 cells with vector expressing a constitutively active form of AKT (see 164730), a major mediator of IGF1 signaling, also stimulated VEGF expression. The IGF1-induced upregulation of VEGF production was associated with activation of AP1 (see JUN, 165160) and HIF1-alpha and was abrogated by phosphatidylinositol 3-kinase inhibitors, a JUN kinase inhibitor, HIF1-alpha antisense oligonucleotide, or geldanamycin, an inhibitor of the heat shock protein-90 molecular chaperone (see 140571), which regulates the 3-dimensional conformation and function of IGF1 receptor and AKT. The authors concluded that IGF1 stimulates VEGF synthesis in thyroid carcinomas in an AKT-dependent pathway via AP1 and HIF1-alpha and that their data provide a framework for clinical use of small-molecule inhibitors, including geldanamycin analogs, to abrogate proangiogenic cascades in thyroid cancer.

VEGF and TGFB1 (190180) have opposing effects on endothelial cells in that TGFB1 induces apoptosis and VEGF protects endothelial cells from apoptosis. However they are often coexpressed in angiogenic tissues, and TGFB1 upregulates VEGF expression. Using bovine and human endothelial cells, Ferrari et al. (2006) found that crosstalk between TGFB1 and VEGF can convert VEGF into a proapoptotic signal through VEGFR2 and p38 MAPK (MAPK14; 600289).

Noguera-Troise et al. (2006) reported that VEGF dynamically regulates tumor endothelial expression of delta-like ligand-4 (DLL4; 605185), which had been shown to be absolutely required for normal embryonic vascular development. To define Dll4 function in tumor angiogenesis, Noguera-Troise et al. (2006) manipulated this pathway in murine tumor models using several approaches. They showed that blockade resulted in markedly increased tumor vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was nonproductive--as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumor growth--even for tumors resistant to anti-VEGF therapy. Thus, Noguera-Troise et al. (2006) concluded that VEGF-induced Dll4 acts as a negative regulator of tumor angiogenesis; its blockade results in the striking uncoupling of tumor growth from vessel density, presenting a novel therapeutic approach even for tumors resistant to anti-VEGF therapies.

Using a transgenic system to conditionally induce Vegf in specific adult mouse organs, Grunewald et al. (2006) showed that Vegf was sufficient for organ homing of circulating mononuclear myeloid cells and was required for their perivascular positioning and retention. Recruited bone marrow-derived circulating cells (RBCCs) summoned by Vegf served a function distinct from endothelial progenitor cells. Retention of RBCCs in close proximity to angiogenic vessels was mediated by Sdf1 (CXCL12; 600835), a chemokine induced by Vegf in activated perivascular myofibroblasts. RBCCs enhanced in situ proliferation of endothelial cells via secreting proangiogenic activities distinct from locally induced activities. Precluding RBCCs strongly attenuated proangiogenic responses to Vegf, and addition of purified RBCCs enhanced angiogenesis in excision wounds. Grunewald et al. (2006) concluded that VEGF-induced recruitment of RBCCs is an integral component of adult neovascularization.

Bock et al. (2007) found that the topical or systemic application of bevacizumab, a recombinant, humanized, monoclonal antibody that binds to VEGFA and prevents VEGFA from ligating to its receptor, could inhibit inflammatory angiogenesis and lymphangiogenesis in the cornea.

Arany et al. (2008) demonstrated that the transcriptional coactivator PGC1A (604517), a potent metabolic sensor and regulator, is induced by a lack of nutrients and oxygen, and that PGC1A powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle. Pgc1A-null mice showed a striking failure to reconstitute blood flow in a normal manner to the limb after an ischemic insult, whereas transgenic expression of PGC1A in skeletal muscle was protective. Surprisingly, the induction of VEGF by PGC1A did not involve the canonical hypoxia response pathway and hypoxia-inducible factor (HIF; see 603348). Instead, PGC1A coactivated the orphan nuclear receptor estrogen-related receptor-alpha (ERRA; 601998) on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene. Thus, PGC1A and ERRA, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates.

Clinical trials of small interfering RNA (siRNA) targeting VEGFA or its receptor VEGFR1 (also called FLT1, 165070) in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration are premised on gene silencing by means of intracellular RNA interference (RNIi). Kleinman et al. (2008) showed instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting nonmammalian genes, nonexpressed genes, nongenomic sequences, pro- and antiangiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNA targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha (147660)/beta (147640) activation. Nontargeted (against nonmammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell surface toll-like receptor-3 (TLR3; 603029), its adaptor TRIF (607601), and induction of interferon-gamma (147570) and interleukin-12 (see 161560). Nontargeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modeled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.

Greenberg et al. (2008) defined a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt vascular smooth muscle cell function. Specifically, under conditions of platelet-derived growth factor (PDGF; see 173430)-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGFR2 (191306) suppresses PDGFRB (173410) signaling in vascular smooth muscle cells through the assembly of a receptor complex consisting of PDGFRB and VEGFR2. Inhibition of VEGFR2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumor cell VEGF disrupts PDGFRB/VEGFR2 complex formation and increases tumor vessel maturation. Greenberg et al. (2008) concluded that their findings underscored the importance of vascular smooth muscle cells/pericytes in neovascularization and revealed a dichotomous role for VEGF and VEGFR2 signaling as both a promoter of endothelial cell function and a negative regulator of vascular smooth muscle cells and vessel maturation.

Stockmann et al. (2008) showed that the deletion of inflammatory cell-derived VEGFA attenuates the formation of a typical high density vessel network, thus blocking the angiogenic switch in solid tumors in mice. Vasculature in tumors lacking myeloid cell-derived VEGFA was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGFA decreased the phosphorylation of VEGFR2 in tumors, even though overall VEGFA levels in the tumors were unaffected. However, deletion of myeloid cell VEGFA resulted in an accelerated tumor progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumor cell death and decreased tumor hypoxia. Furthermore, loss of myeloid cell VEGFA increased the susceptibility of tumors to chemotherapeutic cytotoxicity. Stockmann et al. (2008) concluded that myeloid-derived VEGFA is essential for the tumorigenic alteration of vasculature and signaling to VEGFR2, and that these changes act to retard, not promote, tumor progression.

Ray et al. (2009) reported an RNA switch in the human VEGFA mRNA 3-prime UTR that integrates signals from IFN-gamma (147570) and hypoxia to regulate VEGFA translation in myeloid cells. Analogous to riboswitches, the VEGFA 3-prime UTR undergoes a binary conformational change in response to environmental signals. However, the VEGFA 3-prime UTR switch is metabolite-independent, and the conformational change is dictated by mutually exclusive, stimulus-dependent binding of proteins, namely, the IFN-gamma-activated inhibitor of translation complex and heterogeneous nuclear ribonucleoprotein L (HNRNPL; 603083). Ray et al. (2009) speculated that the VEGFA switch represents the founding member of a family of signal-mediated, protein-dependent RNA switches that evolved to regulate gene expression in multicellular animals in which the precise integration of disparate inputs may be more important than the rapidity of response.

Using flow cytometric, RT-PCR, and Western blot analysis, Basu et al. (2010) determined that CD45RO (PTPRC; 151460)-positive CD4-positive memory T lymphocytes expressed VEGF receptors KDR (191306) and FLT1 (165070) and that VEGF increased the phosphorylation and activation of ERK (see MAPK3, 601795) and AKT in these cells. VEGF-mediated signaling was inhibited by specific siRNA or pharmacologic inhibitor. VEGF also augmented mitogen-induced production of IFNG (147570) and memory T cell chemotaxis. Basu et al. (2010) concluded that VEGF and KDR have important roles in CD45RO-positive memory T cell responses.

Beck et al. (2011) used a mouse model of skin tumors to investigate the impact of the vascular niche and VEGF signaling on controlling the stemness of squamous skin tumors during the early stages of tumor progression. They showed that cancer stem cells of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking Vegfr2 caused tumor regression not only by decreasing the microvascular density, but also by reducing cancer stem cell pool size and impairing cancer stem cell renewal properties. Conditional deletion of Vegfa in tumor epithelial cells caused tumors to regress, whereas Vegf overexpression by tumor epithelial cells accelerated tumor growth. In addition to its well-known effect on angiogenesis, Vegf affected skin tumor growth by promoting cancer stemness and symmetric cancer stem cell division, leading to cancer stem cell expansion. Moreover, deletion of neuropilin-1 (NRP1; 602069), a VEGF coreceptor expressed in cutaneous cancer stem cells, blocked Vegf's ability to promote cancer stemness and renewal. Beck et al. (2011) concluded that their results identified a dual role for tumor cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for cancer stem cells, and by directly affecting cancer stem cells through NRP1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of Nrp1 in normal epidermis prevents skin tumor initiation.

Benedito et al. (2012) used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 (605185) protein expression in retinal tip cells is only weakly modulated by VEGFR2 (191306) signaling. Surprisingly, Notch (190198) inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3 (136352), the main receptor for VEGFC (601528), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. Benedito et al. (2012) concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling.

In the mouse, Rao et al. (2013) identified a light response pathway that regulates both regression of embryonic hyaloid vasculature and formation of retinal vasculature. Rao et al. (2013) showed that in mice with mutations in the Opn4 (606665) gene, or that are dark-reared from late gestation, the hyaloid vessels are persistent at 8 days postpartum and the retinal vasculature overgrows. Rao et al. (2013) provided evidence that these vascular anomalies are explained by a light response pathway that suppresses retinal neuron number, limits hypoxia, and as a consequence holds local expression of VEGFA in check. Rao et al. (2013) also showed that the light response for this pathway occurs in late gestation at about embryonic day 16 and requires the photopigment in the fetus and not the mother. Measurements showed that visceral cavity photon flux is probably sufficient to activate melanopsin-expressing retinal ganglion cells in the mouse fetus. Rao et al. (2013) concluded that light, the stimulus for function of the mature eye, is also critical in preparing the eye for vision by regulating retinal neuron number and initiating a series of events that ultimately pattern the ocular blood vessels.

Leng et al. (2014) identified a microRNA-718 (MIR718; 300929) target site in the 3-prime UTR of the human VEGFA transcript. Quantitative RT-PCR and Western blot analysis showed that expression of MIR718 was downregulated, whereas expression of VEGF mRNA and protein was upregulated, in ovarian cancer specimens. Reporter gene assays revealed that MIR718 downregulated expression from the VEGFA 3-prime UTR, but not when the MIR718-binding site was mutated. MIR718 overexpression inhibited cell proliferation and invasive potential and promoted apoptosis in several ovarian cancer cell lines, and restoration of VEGF expression reversed these effects. MIR718 overexpression also inhibited tumor growth following subcutaneous injection of ovarian tumor cells in mice.

Colegio et al. (2014) showed that lactic acid produced by tumor cells, as a byproduct of aerobic or anaerobic glycolysis, has a critical function in signaling, through inducing the expression of VEGF and the M2-like polarization of tumor-associated macrophages. The authors also demonstrated that this effect of lactic acid is mediated by hypoxia-inducible factor 1-alpha (HIF1A; 603348). Finally, they showed that the lactate-induced expression of arginase-1 (ARG1; 608313) by macrophages has an important role in tumor growth. Colegio et al. (2014) concluded that their findings identified a mechanism of communication between macrophages and their client cells, including tumor cells. This communication likely evolved to promote homeostasis in normal tissues but can also be engaged in tumors to promote their growth.

POEMS Syndrome

POEMS syndrome, also known as Crow-Fukase syndrome (Crow, 1956; Shimpo, 1968), is a rare multisystem disorder of obscure pathogenesis and no conspicuous heritability with the cardinal features of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (Bardwick et al., 1980; Nakanishi et al., 1984; Miralles et al., 1992). It is usually associated with plasma cell dyscrasia and osteosclerotic bone lesions. Watanabe et al. (1998) suggested that overproduction of VEGF may explain the microangiopathy, neovascularization, and accelerated vasopermeability that occur in this syndrome. They found that serum VEGF levels in 10 patients with POEMS syndrome were about 15 to 30 times higher than those in control subjects or patients with Guillain-Barre syndrome (139393), chronic inflammatory demyelinating polyneuropathy, and other neurologic disorders. CSF levels of VEGF were, however, similar to those found in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy.

Niimi et al. (2000) described a patient with POEMS syndrome and pulmonary hypertension associated with extremely high concentrations of VEGF in the serum and normal levels of IL1B (147720), IL6, and TNF-alpha (TNF; 191160), which were previously thought to be mediators of pulmonary hypertension in this disorder. After prednisolone therapy, pulmonary hypertension disappeared with a dramatic decrease in serum VEGF. Diduszyn et al. (2002) reported bilateral visual loss in a patient with optic disc drusen (177800) and POEMS syndrome. Visual loss occurred when the patient developed peripapillary choroidal neovascularization and subsequent hemorrhage in the subretinal space. The authors hypothesized that the elevated VEGF due to POEMS syndrome might have played a role in the development of choroidal neovascularization.

Among 161 patients with various forms of neuropathy, including 6 with POEMS syndrome, Nobile-Orazio et al. (2009) found significantly increased serum VEGF levels in the patients with POEMS compared to other patient groups. A significant, though less marked, increase in serum VEGF was found in patients with Guillain-Barre syndrome, chronic inflammatory demyelinating polyradioculoneuropathy, and neuropathy associated with increased IgM compared to other groups. The findings suggested a role for VEGF in immune-mediated neuropathies.

In a retrospective analysis of 208 patients with POEMS syndrome, Dupont et al. (2009) found that 19 had a cerebral infarction at a median age of 53 years, yielding an estimated 5-year risk of cerebral infarction in POEMS syndrome of 13.4%. Risk factors included plasma cell proliferation in the bone marrow and increased platelet count. Aggressive treatment of modifiable risk factors was successful in preventing further strokes. Angiographic studies showed abnormalities in the cervical and proximal intracranial vasculature.

▼ Biochemical Features

Bostrom et al. (2009) described an antibody with an antigen binding site that binds 2 distinct proteins with high affinity. They isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor-2 (HER2; 164870), on the basis of its ability to simultaneously interact with VEGF. Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the 2 antigens. An affinity-improved version of bH1 inhibited both HER2- and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. The authors argued that such 'two-in-one' antibodies challenge the monoclonal antibody paradigm of 1 binding site, 1 antigen.

▼ Mapping

Mattei et al. (1996) used radioactive in situ hybridization to map VEGF to 6p21-p12. Wei et al. (1996) reported the localization of the VEGF gene to chromosome 6p12 by FISH. Vincenti et al. (1996) also used in situ hybridization to map the VEGF gene to 6p21.3.

▼ Molecular Genetics

Role in Diabetic Retinopathy

Awata et al. (2002) identified 7 polymorphisms of the VEGF gene in the promoter region and 5-prime and 3-prime untranslated regions. The genotype distribution of one of these (-634G-C; rs2010963; 192240.0001) differed significantly between type 2 diabetes (125853) patients without retinopathy and those with any retinopathy, and the C allele was significantly associated with the presence of retinopathy (see 603933).

Possible Role in Amyotrophic Lateral Sclerosis

Lambrechts et al. (2003) followed up on the observation that reduced expression of VEGF produced in transgenic mice by gene targeting to delete the hypoxia-response element (HRE) in the promoter region of the gene (Oosthuyse et al., 2001) predisposed the mice to adult-onset progressive motoneuron degeneration, with many neuropathologic and clinical signs reminiscent of human amyotrophic lateral sclerosis (ALS; 105400). In a metaanalysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England using the -2578C-A (rs699947; 192240.0002), -634G-C, and -1154G-A (rs1570360) SNPs, Lambrechts et al. (2003) found that subjects homozygous for haplotypes -2578A/-1154A/-634G (AAG) or -2578A/-1154G/-634G (AGG) in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes were associated with lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, internal ribosomal entry site (IRES)-mediated VEGF expression, and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1-G93A (147450.0008) mice crossbred with mice with the deletion of the HRE in the promoter region of the Vegfa gene died earlier due to more severe motoneuron degeneration. Moreover, mice with the HRE deletion were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings suggested that VEGF may be is a modifier of motoneuron degeneration in human ALS. Although the VEGF treatment data related only to acute spinal cord ischemia, they raised the intriguing question whether more long-term treatment with VEGF might delay the onset or slow the progression of adult-onset motoneuron degeneration as well. Van Vught et al. (2005) failed to find an association between the VEGF at-risk haplotypes AAG and AGG reported by Lambrechts et al. (2003) and ALS among 373 ALS patients and 615 controls in the Netherlands. Fernandez-Santiago et al. (2006) did not observe any significant association between SNPs or haplotypes in the VEGF gene and ALS among 580 patients and 628 controls in Germany. Chen et al. (2006) also did not observe any association between promoter polymorphisms in the VEGF gene or VEGF haplotypes and sporadic ALS among 1,122 patients.

Lambrechts et al. (2009) performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype (rs699947; 192240.0002), which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing.

Golenia et al. (2010) did not find an association between SNPs in the VEGF gene and ALS in a study of 271 unrelated Polish patients with sporadic ALS and 464 age- and gender-matched controls. In addition, there was no significant difference in plasma levels of VEGF among 60 sporadic ALS patients compared to 75 controls.

Possible Role in Pseudoxanthoma Elasticum-Related Retinopathy

Pseudoxanthoma elasticum (PXE; 264800) is a heritable disorder affecting the skin, eyes and cardiovascular system caused by mutation in the ABCC6 gene (603234). Choroidal neovascularization (CNV) in PXE-associated retinopathy is believed to be mediated by the action of VEGF. Zarbock et al. (2009) evaluated the distribution of 10 SNPs in the promoter and coding region of the VEGFA gene in DNA samples from 163 German patients affected by PXE and in 163 healthy control subjects. Haplotype analysis identified an 8-SNP haplotype CTGGCCCC that was associated with PXE. Furthermore, 5 SNPs showed significant association with severe retinopathy. The most significant single SNP association was -460C-T (rs833061, OR = 3.83, 95% CI 2.01-7.31, corrected p = 0.0003). Logistic regression analysis identified the rs833061 and 674C-T variant (rs1413711; OR = 3.21, 95% CI 1.70-6.02, corrected p = 0.004) as independent risk factors for development of severe retinopathy. Zarbock et al. (2009) suggested an involvement of VEGF in the pathogenesis of ocular PXE manifestations.

Role in Other Disorders

Tetralogy of Fallot (TOF; 187500), one of the most common forms of congenital heart disease, occurs as part of the DiGeorge syndrome (188400). In most cases, TOF is not caused by chromosomal or single gene defects, but presumably results from genetic variations of several susceptibility factors. Lambrechts et al. (2005) found that 2 common SNPs in the VEGF promoter and 1 common SNP in the leader sequence, which are known to lower VEGF levels, increased the risk of TOF. Genotyping of 148 families with isolated, nonsyndromic TOF revealed that a low-VEGF 'AAG' haplotype (-2578A, -1154A, -634G) was overtransmitted to affected children (p = 0.008). Metaanalysis of patients with isolated, nonsyndromic TOF and DiGeorge syndrome patients with TOF revealed that the 'AAG' haplotype increased the risk of TOF 1.8-fold (p = 0.0008). VEGF was said to be the first modifier gene identified for TOF.

Howell et al. (2005) genotyped 984 patients from the Southampton Atherosclerosis Study for the VEGF -2578C-A, -1154G-A, and -634G-C SNPs and found that the distribution of the -2578 polymorphism differed significantly in patients without myocardial infarction when stratified according to the number of diseased coronary arteries; the AA genotype was a risk factor and CC was protective.

Del Bo et al. (2005) presented evidence suggesting that the VEGF -2578A/A genotype confers an increased risk for the development of Alzheimer disease (AD; see 104300).

▼ Animal Model

Carmeliet et al. (1996) and Ferrara et al. (1996) observed the effects of targeted disruption of the Vegf gene in mice. They found that formation of blood vessels was abnormal but not abolished in heterozygous Vegf-deficient embryos and even more impaired in homozygous Vegf-deficient embryos, resulting in death at midgestation. Similar phenotypes were observed in F(1) heterozygous embryos generated by germline transmission. They interpreted their results as indicating a tight dose-dependent regulation of embryonic vessel development by Vegf. Mice homozygous for mutations that inactivate either of the 2 Vegf receptors also die in utero. However, 1 or more ligands other than Vegf might activate such receptors. Ferrara et al. (1996) likewise reported the unexpected finding that loss of a single Vegf allele is lethal in a mouse embryo between days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, Vegf-null embryonic stem cells exhibited a dramatically reduced ability to form tumors in nude mice.

Springer et al. (1998) investigated the effects of long-term stable production of the VEGF protein by myoblast-mediated gene transfer. Myoblasts were transduced with a retrovirus carrying a murine Vegf164 cDNA and injected into mouse leg muscles. Continuous Vegf delivery resulted in hemangiomas containing localized networks of vascular channels. Springer et al. (1998) demonstrated that myoblast-mediated VEGF gene delivery can lead to complex tissues of multiple cell types in normal adults. Exogenous VEGF gene expression at high levels or of long duration can also have deleterious effects. A physiologic response to VEGF was observed in nonischemic muscle; the response in the adult did not appear to occur via angiogenesis and may have involved a mechanism related to vasculogenesis, or de novo vessel development. Springer et al. (1998) proposed that VEGF may have different effects at different concentrations: angiogenesis or vasculogenesis.

Fukumura et al. (1998) established a line of transgenic mice expressing the green fluorescent protein (GFP) under the control of the promoter for VEGF. Mice bearing the transgene showed green cellular fluorescence around the healing margins and throughout the granulation tissue of superficial ulcerative wounds. Implantation of solid tumors in the transgenic mice led to an accumulation of green fluorescence resulting from tumor induction of host VEGF promoter activity. With time, the fluorescent cells invaded the tumor and could be seen throughout the tumor mass. Spontaneous mammary tumors induced by oncogene expression in the VEGF-GFP mouse showed strong stromal, but not tumor, expression of GFP. In both wound and tumor models, the predominant GFP-positive cells were fibroblasts.

To determine the role of VEGF in endochondral bone formation, Gerber et al. (1999) inactivated VEGF through the systemic administration of a soluble receptor chimeric protein in 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of the hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation, and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage, and normalization of the growth plate architecture. These findings indicated to Gerber et al. (1999) that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Gerber et al. (1999) concluded that VEGF is an essential coordinator of chondrocyte death, chondroclast function, ECM remodeling, angiogenesis, and bone formation in the growth plate.

Thurston et al. (1999) compared transgenic mice overexpressing either Vegf or Ang1 in the skin. Vegf-induced blood vessels were leaky, whereas those induced by Ang1 were not. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and Vegf had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Thurston et al. (1999) concluded that ANG1, therefore, may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEFG and, in combination with VEGF, for promoting growth of nonleaky vessels.

Sone et al. (2001) administered VEGF-neutralizing antibodies to mice with collagen-induced arthritis, which has many immunologic and pathologic similarities to human rheumatoid arthritis. Anti-VEGF antibody administered prior to disease onset significantly delayed the development of arthritis and decreased clinical score and paw thickness as well as histologic severity. On the other hand, the frequency of occurrence of disease compared to either the control group administered saline or normal rabbit immunoglobulin was not altered. Anti-VEGF antibody also significantly ameliorated clinical and histopathologic parameters even when administered after disease onset. Sone et al. (2001) suggested that their results indicated a possible therapeutic potential for anti-VEGF treatment in human arthritis.

Giordano et al. (2001) investigated the role of the cardiac myocyte as a mediator of paracrine signaling in the heart. They generated conditional knockout mice with cardiomyocyte-specific deletion of exon 3 of the VEGFA gene, using Cre/lox technology, i.e., by 'floxing' of VEGF exon 3 in embryonic stem cells. The hearts of these mice had fewer coronary microvessels, thinned ventricular walls, depressed basal contractile function, induction of hypoxia-responsive genes involved in energy metabolism, and an abnormal response to beta-adrenergic stimulation.

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the VEGF promoter. Oosthuyse et al. (2001) reported that in 'knock-in' mice in which the hypoxia-response element sequence in the Vegf promoter had been deleted by means of targeted Cre/loxP recombination, hypoxic Vegf expression in the spinal cord was reduced and resulted in adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis (105400). Neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, the Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegfr2 and neuropilin-1 (602069). The results indicated that chronic vascular insufficiency and possibly insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.

De Fraipont et al. (2000) measured the cytosolic concentrations of 3 proteins involved in angiogenesis, namely, platelet-derived endothelial cell growth factor (PDECGF; 131222), VEGFA, and thrombospondin-1 (THBS1; 188060) in a series of 43 human sporadic adrenocortical tumors. The tumors were classified as adenomas, transitional tumors, or carcinomas. PDECGF/thymidine phosphorylase levels were not significantly different among these 3 groups. One hundred percent of the adenomas and 73% of the transitional tumors showed VEGFA concentrations under the threshold value of 107 ng/g protein, whereas 75% of the carcinomas had VEGFA concentrations above this threshold value. Similarly, 89% of the adenomas showed THBS1 concentrations above the threshold value of 57 microg/g protein, whereas only 25% of the carcinomas and 33% of the transitional tumor samples did so. IGF2 (147470) overexpression, a common genetic alteration of adrenocortical carcinomas, was significantly correlated with higher VEGFA and lower THBS1 concentrations. The authors concluded that a decrease in THBS1 expression is an event that precedes an increase in VEGFA expression during adrenocortical tumor progression. The population of premalignant tumors with low THBS1 and normal VEGFA levels could represent a selective target for antiangiogenic therapies.

Ylikorkala et al. (2001) generated Lkb1 -/- mice by targeted disruption. The mice died at midgestation with various vascular abnormalities affecting the embryo as well as the placenta. These phenotypes were associated with tissue-specific deregulation of VEGF expression, including a marked increase in the amount of VEGF mRNA. Moreover, VEGF production in cultured Lkb1 -/- fibroblasts was elevated in both normoxic and hypoxic conditions. Ylikorkala et al. (2001) concluded that their findings place Lkb1 in the VEGF signaling pathway and suggested that the vascular defects accompanying Lkb1 loss are mediated at least in part by VEGF.

Capillary nonperfusion is a hallmark of diabetic retinopathy and other retinal ischemic diseases. Hofman et al. (2001) studied capillary nonperfusion of the retina in a monkey model of VEGF-induced retinopathy. Luminal narrowing caused by endothelial cell hypertrophy occurred in the deep retinal capillary plexus in the VEGF-induced retinopathy in monkeys, suggesting a causal role of endothelial cell hypertrophy in the pathogenesis of VEGF-induced retinal capillary closure. The authors suggested that a similar mechanism might operate in humans with retinal conditions associated with VEGF overexpression and ischemia.

Krzystolik et al. (2002) evaluated the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward VEGF (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV). They found that intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already-formed CNV with no significant toxic effects. The authors concluded that their study provided the nonclinical proof of principle for ongoing clinical studies of intravitreally-injected rhuFab VEGF in patients with CNV due to age-related macular degeneration (see 153800).

In laser-injury studies in mice, Nozaki et al. (2006) observed that injury-induced CNV was increased by excess Vegf before injury but was suppressed by Vegf after injury. This effect was mediated via Vegfr1 (FLT1; 165070) activation and Vegfr2 (KDR; 191306) deactivation: excess Vegf increased CNV before injury because Vegfr1 activation was silenced by Sparc (182120), and a transient decline in Sparc after injury created a temporal window in which Vegf signaling was routed primarily through Vegfr1.

Stalmans et al. (2003) reported that absence of the 164-amino acid isoform of Vegf (Vegf164), the only one that binds neuropilin-1, causes birth defects in mice reminiscent of those found in patients with deletion of 22q11. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. VEGF interacted with Tbx1 (602054), as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down Vegf levels enhanced the pharyngeal arch artery defects induced by Tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. Stalmans et al. (2003) concluded that genetic data in mouse, fish, and human indicated that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.

Ruhrberg et al. (2002) engineered mice to exclusively express a Vegf isoform that lacks the heparin-binding domain and is therefore deficient in extracellular matrix interaction. The absence of this domain altered the extracellular localization of Vegf and altered the distribution of endothelial cells within the growing vasculature. Instead of being recruited into additional branches, nascent endothelial cells were integrated within existing vessels to increase lumen caliber. Disruption of the normal Vegf concentration gradient also misguided the directed extension of endothelial cell filopodia. On the other hand, embryos harboring only the heparin-binding domain showed opposite defects, including excess endothelial filopodia and abnormally thin vessel branches in ectopic sites.

Carpenter et al. (2003) studied pulmonary edema formation in rats deficient for endothelin receptor type B (EDNRB; 131244). EDNRB -/- rats had significantly more lung vascular leak than heterozygotes or controls. Hypoxia increased vascular leak regardless of genotype, and hypoxic EDNRB-deficient rats leaked more than hypoxic controls. EDNRB-deficient rats had higher lung endothelin levels in both normoxia and hypoxia. Lung hypoxia-inducible factor-1-alpha (HIF1A; 603348) and VEGF levels were greater in the EDNRB-deficient rats in both normoxia and hypoxia, and both levels were reduced by endothelin receptor type A (EDNRA; 131243) antagonism. Both EDNRA blockade and VEGF antagonism reduced vascular leak in hypoxic EDNRB-deficient rats. Carpenter et al. (2003) concluded that EDNRB-deficient rats display an exaggerated lung vascular protein leak in normoxia, that hypoxia exacerbates that leak, and that this effect is in part attributable to an endothelin-mediated increase in lung VEGF content.

Azzouz et al. (2004) reported that a single injection of a VEGF-expressing lentiviral vector into various muscles delayed onset and slowed progression of amyotrophic lateral sclerosis (ALS; 105400) in mice engineered to overexpress the gene encoding the mutated G93A form of SOD1 (147450.0008), even when treatment was initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30% without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field to that time.

Lee et al. (2004) generated transgenic mice overexpressing Vegf165 and evaluated the role of Vegf in antigen-induced Th2 inflammation. Vegf potently induced, through Il13 (147683)-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia, and airway hyperresponsiveness. The phenotype was associated with enhanced respiratory antigen sensitization and Th2 inflammation and increased numbers of activated DC2 dendritic cells. Lee et al. (2004) concluded that VEGF stimulates inflammation, airway and vascular remodeling, and physiologic dysregulation that augments antigen sensitization and Th2 inflammation through IL13-dependent and -independent mechanisms.

Tam et al. (2006) observed that inhibition of Vegf by diverse methods increased hematocrit in both mouse and primate models. Inhibition of Vegf induced hepatic synthesis of erythropoietin (EPO; 133170) through an Hif1a-independent mechanism in parallel with suppression of renal Epo mRNA. Hepatocyte-specific deletion of the Vegfa gene in mice and hepatocyte-endothelial cell cocultures indicated that blockade of Vegf induced hepatic Epo by interfering with homeostatic Vegfr2-dependent paracrine signaling between hepatocytes and endothelial cells. Tam et al. (2006) concluded that VEGF is a negative regulator of hepatic EPO synthesis and erythropoiesis.

In mice with experimental autoimmune encephalitis (EAE), a mouse model of a central nervous system inflammatory disease, Argaw et al. (2009) observed widespread breakdown of the blood-brain barrier (BBB) associated with upregulation of astrocyte-derived Vegf and decreased expression of Cldn5 (602101) and occludin (Ocln; 602876) in the microvascular endothelium. VEGF was found to specifically downregulate CLDN5 and OCLN mRNA and protein in cultured human brain microvessel endothelial cells. Microinjection of VEGF in mouse cerebral cortex disrupted Cldn5 and Ocln and induced loss of barrier function. Functional studies revealed that expression of recombinant Cldn5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in permeability, whereas recombinant Ocln expressed under the same promoter was not protective. The findings implicated VEGF-mediated disruption of endothelial CLDN5 as a significant mechanism of BBB breakdown in the inflamed central nervous system.

Kokki et al. (2018) found that induced expression of human VEGF in mouse eye resulted in several features of age-related macular degeneration and vascular abnormalities consistent with choroidal neovascularization. Immunohistochemical staining showed that human VEGF was expressed in Muller cells and photoreceptors, but also in choroidal neovascularization and fibrovascular membranes of mouse eye. Human VEGF expression was also detected in off-target organs and plasma.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

Table View ClinVar

.0001 MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 1

VEGFA, -634G-C, (rs2010963)

RCV000013007...

Awata et al. (2002) studied the -634G-C polymorphism of the VEGF gene in type 2 diabetes (125853) patients with proliferative and nonproliferative diabetic retinopathy (MVCD1; 603933) and compared the genotype frequencies with controls (patients without retinopathy). The odds ratio for the CC genotype to the GG genotype was 3.20 (95% CI, 1.45-7.05; p = 0.0046). The -634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (p = 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the nonproliferative and proliferative diabetic retinopathy groups. Logistic regression analysis revealed that the -634G-C polymorphism was strongly associated with an increased risk of retinopathy. Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the polymorphism than in those with other genotypes.

.0002 RECLASSIFIED - VASCULAR ENDOTHELIAL GROWTH FACTOR A POLYMORPHISM

VEGFA, -2578C-A, (rs699947)

RCV000013008

This variant, formerly titled ATHEROSCLEROSIS, SUSCEPTIBILITY TO (with the INCLUDED titles of Alzheimer Disease, Susceptibility to and Amyotrophic Lateral Sclerosis in Males, Susceptibility to) has been reclassified as a polymorphism based on a review of the refSNP Cluster Report (May 14, 2018) by Hamosh (2018): rs699947 had an MAF/minor allele count of 0.3245/1625 in the 1000 Genomes Project database and 0.3850/48341 in the TOPMED Study.

Atherosclerosis, Susceptibility to

Howell et al. (2005) genotyped 941 patients from the Southampton Atherosclerosis Study for the VEGF -2578C-A polymorphism and found a significantly different distribution of genotypes in patients without myocardial infarction when stratified according to number of diseased coronary arteries; there was also an association with mean number of stenotic segments in the same patient group. The AA genotype was a risk factor and CC was protective.

Alzheimer Diseae, Susceptibility to

Del Bo et al. (2005) presented evidence suggesting that variation in the expression of VEGF may play a role in the development of Alzheimer disease (AD; see 104300). In a case-control study of 249 Italian patients with sporadic AD, they found that 23.7% of the patients had the -2578A/A genotype compared to 14.7% of controls, yielding an adjusted odds ratio of 3.37. No difference in the serum levels of VEGF was detected between patients and controls. Del Bo et al. (2005) postulated that the -2578A/A genotype may confer greater risk for AD by reducing the neuroprotective effect of VEGF.

Amyotrophic Lateral Sclerosis in Males, Susceptibility to

Lambrechts et al. (2009) performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing.

▼ REFERENCES

Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., Cheresh, D. A. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301: 94-96, 2003. [PubMed: 12843393, related citations] [Full Text]
Arany, Z., Foo, S.-Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H., Rosenzweig, A., Spiegelman, B. M. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1-alpha. Nature 451: 1008-1012, 2008. [PubMed: 18288196, related citations] [Full Text]
Argaw, A. T., Gurfein, B. T., Zhang, Y., Zameer, A., John, G. R. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc. Nat. Acad. Sci. 106: 1977-1982, 2009. [PubMed: 19174516, images, related citations] [Full Text]
Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plaisance, S., De Mol, M., Bono, F., Kliche, S., Fellbrich, G., and 16 others. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Med. 9: 936-943, 2003. [PubMed: 12796773, related citations] [Full Text]
Awata, T., Inoue, K., Kurihara, S., Ohkubo, T., Watanabe, M., Inukai, K., Inoue, I., Katayama, S. A common polymorphism in the 5-prime-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51: 1635-1639, 2002. [PubMed: 11978667, related citations] [Full Text]
Azzouz, M., Ralph, G. S., Storkebaum, E., Walmsley, L. E., Mitrophanous, K. A., Kingsman, S. M., Carmeliet, P., Mazarakis, N. D. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429: 413-417, 2004. [PubMed: 15164063, related citations] [Full Text]
Bainbridge, J. W. B., Jia, H., Bagherzadeh, A., Selwood, D., Ali, R. R., Zachary, I. A peptide encoded by exon 6 of VEGF (EG3306) inhibits VEGF-induced angiogenesis in vitro and ischaemic retinal neovascularisation in vivo. Biochem. Biophys. Res. Commun. 302: 793-799, 2003. [PubMed: 12646239, related citations] [Full Text]
Bardwick, P. A., Zvaifler, N. J., Gill, G. N., Newman, D., Greenway, G. D., Resnick, D. L. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine 59: 311-322, 1980. [PubMed: 6248720, related citations] [Full Text]
Basu, A., Hoerning, A., Datta, D., Edelbauer, M., Stack, M. P., Calzadilla, K., Pal, S., Briscoe, D. M. Cutting edge: vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production. J. Immunol. 184: 545-549, 2010. [PubMed: 20008289, images, related citations] [Full Text]
Basu, S., Nagy, J. A., Pal, S., Vasile, E., Eckelhoefer, I. A., Bliss, V. S., Manseau, E. J., Dasgupta, P. S., Dvorak, H. F., Mukhopadhyay, D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nature Med. 7: 569-574, 2001. [PubMed: 11329058, related citations] [Full Text]
Beck, B., Driessens, G., Goossens, S., Youssef, K. K., Kuchnio, A., Caauwe, A., Sotiropoulou, P. A., Loges, S., Lapouge, G., Candi, A., Mascre, G., Drogat, B., Dekoninck, S., Haigh, J. J., Carmeliet, P., Blanpain, C. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478: 399-403, 2011. [PubMed: 22012397, related citations] [Full Text]
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484: 110-114, 2012. [PubMed: 22426001, related citations] [Full Text]
Bock, F., Onderka, J., Dietrich, T., Bachmann, B., Kruse, F. E., Paschke, M., Zahn, G., Cursiefen, C. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest. Ophthal. Vis. Sci. 48: 2545-2552, 2007. [PubMed: 17525183, related citations] [Full Text]
Bostrom, J., Yu, S.-F., Kan, D., Appleton, B. A., Lee, C. V., Billeci, K., Man, W., Peale, F., Ross, S., Wiesmann, C., Fuh, G. Variants of the antibody Herceptin that interact with HER2 and VEGF at the antigen binding site. Science 323: 1610-1614, 2009. [PubMed: 19299620, related citations] [Full Text]
Cao, L., Jiao, X., Zuzga, D. S., Liu, Y., Fong, D. M., Young, D., During, M. J. VEGF links hippocampal activity with neurogenesis, learning and memory. Nature Genet. 36: 827-835, 2004. [PubMed: 15258583, related citations] [Full Text]
Carmeliet, P., Ferreira, V., Breler, G., Pollefeyt, S., Kleckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declercq, C., Pawling, J., Moons, L., Collen, D., Risau, W., Nagy, A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435-439, 1996. [PubMed: 8602241, related citations] [Full Text]
Carpenter, T., Schomberg, S., Steudel, W., Ozimek, J., Colvin, K., Stenmark, K., Ivy, D. D. Endothelin B receptor deficiency predisposes to pulmonary edema formation via increased lung vascular endothelial cell growth factor expression. Circ. Res. 93: 456-463, 2003. [PubMed: 12919946, related citations] [Full Text]
Chen, W., Saeed, M., Mao, H., Siddique, N., Dellefave, L., Hung, W.-Y., Deng, H.-X., Sufit, R. L., Heller, S. L., Haines, J. L., Pericak-Vance, M., Siddique, T. Lack of association of VEGF promoter polymorphisms with sporadic ALS. Neurology 67: 508-510, 2006. [PubMed: 16894118, related citations] [Full Text]
Colegio, O. R., Chu, N.-Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., Cyrus, N., Brokowski, C. E., Eisenbarth, S. C., Phillips, G. M., Cline, G. W., Phillips, A. J., Medzhitov, R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513: 559-563, 2014. [PubMed: 25043024, images, related citations] [Full Text]
Crow, R. S. Peripheral neuritis in myelomatosis. Brit. Med. J. 2: 802-804, 1956. [PubMed: 13364332, related citations] [Full Text]
Dantz, D., Bewersdorf, J., Fruehwald-Schultes, B., Kern, W., Jelkmann, W., Born, J., Fehm, H. L., Peters, A. Vascular endothelial growth factor: a novel endocrine defensive response to hypoglycemia. J. Clin. Endocr. Metab. 87: 835-840, 2002. [PubMed: 11836329, related citations] [Full Text]
de Fraipont, F., El Atifi, M., Gicquel, C., Bertagna, X., Chambaz, E. M., Feige, J. J. Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. J. Clin. Endocr. Metab. 85: 4734-4741, 2000. [PubMed: 11134136, related citations] [Full Text]
Del Bo, R., Scarlato, M., Ghezzi, S., Martinelli Boneschi, F., Fenoglio, C., Galbiati, S., Virgilio, R., Galimberti, D., Galimberti, G., Crimi, M., Ferrarese, C., Scarpini, E., Bresolin, N., Comi, G. P. Vascular endothelial growth factor gene variability is associated with increased risk for AD. Ann. Neurol. 57: 373-380, 2005. [PubMed: 15732116, related citations] [Full Text]
Diduszyn, J. M., Quillen, D. A., Cantore, W. A., Gardner, T. W. Optic disk drusen, peripapillary choroidal neovascularization, and POEMS syndrome. Am. J. Ophthal. 133: 275-276, 2002. [PubMed: 11812439, related citations] [Full Text]
Dupont, S. A., Dispenzieri, A., Mauermann, M. L., Rabenstein, A. A., Brown, R. D., Jr. Cerebral infarction in POEMS syndrome: incidence, risk factors, and imaging characteristics. Neurology 73: 1308-1312, 2009. [PubMed: 19841383, related citations] [Full Text]
Fernandez-Santiago, R., Sharma, M., Mueller, J. C., Gohlke, H., Illig, T., Anneser, J., Munch, C., Ludolph, A., Kamm, C., Gasser, T. Possible gender-dependent association of vascular endothelial growth factor (VEGF) gene and ALS. Neurology 66: 1929-1931, 2006. [PubMed: 16801663, related citations] [Full Text]
Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, K. S., Powell-Braxton, L., Hillan, K. J., Moore, M. W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439-442, 1996. [PubMed: 8602242, related citations] [Full Text]
Ferrara, N., Henzel, W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161: 851-858, 1989. [PubMed: 2735925, related citations] [Full Text]
Ferrari, G., Pintucci, G., Seghezzi, G., Hyman, K., Galloway, A. C., Mignatti, P. VEGF, a prosurvival factor, acts in concert with TGF-beta-1 to induce endothelial cell apoptosis. Proc. Nat. Acad. Sci. 103: 17260-17265, 2006. [PubMed: 17088559, images, related citations] [Full Text]
Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1: 27-31, 1995. [PubMed: 7584949, related citations] [Full Text]
Fukumura, D., Xavier, R., Sugiura, T., Chen, Y., Park, E.-C., Lu, N., Selig, M., Nielsen, G., Taksir, T., Jain, R. K., Seed, B. Tumor induction of VEGF promoter activity in stromal cells. Cell 94: 715-725, 1998. [PubMed: 9753319, related citations] [Full Text]
Funatsu, H., Yamashita, H., Noma, H., Mimura, T., Yamashita, T., Hori, S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am. J. Ophthal. 133: 70-77, 2002. [PubMed: 11755841, related citations] [Full Text]
Gerber, H.-P., Malik, A. K., Solar, G. P., Sherman, D., Liang, X. H., Meng, G., Hong, K., Marsters, J. C., Ferrara, N. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417: 954-958, 2002. [PubMed: 12087404, related citations] [Full Text]
Gerber, H.-P., Vu, T. H., Ryan, A. M., Kowalski, J., Werb, Z., Ferrara, N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5: 623-628, 1999. [PubMed: 10371499, related citations] [Full Text]
Geva, E., Ginzinger, D. G., Zaloudek, C. J., Moore, D. H., Byrne, A., Jaffe, R. B. Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J. Clin. Endocr. Metab. 87: 4213-4224, 2002. [PubMed: 12213874, related citations] [Full Text]
Giordano, F. J., Gerber, H.-P., Williams, S.-P., VanBruggen, N., Bunting, S., Ruiz-Lozano, P., Gu, Y., Nath, A. K., Huang, Y., Hickey, R., Dalton, N., Peterson, K. L., Ross, J., Jr., Chien, K. R., Ferrara, N. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc. Nat. Acad. Sci. 98: 5780-5785, 2001. [PubMed: 11331753, images, related citations] [Full Text]
Gogat, K., Le Gat, L., Van Den Berghe, L., Marchant, D., Kobetz, A., Gadin, S., Gasser, B., Quere, I., Abitbol, M., Menasche, M. VEGF and KDR gene expression during human embryonic and fetal eye development. Invest. Ophthal. Vis. Sci. 45: 7-14, 2004. [PubMed: 14691147, related citations] [Full Text]
Golenia, A., Tomik, B., Zawislak, D., Wolkow, P., Dziubek, A., Sado, M., Szczudlik, A., Figlewicz, D. A., Slowik, A. Lack of association between VEGF gene polymorphisms and plasma VEGF levels and sporadic ALS. Neurology 75: 2035-2037, 2010. [PubMed: 21115961, related citations] [Full Text]
Gomez-Manzano, C., Fueyo, J., Jiang, H., Glass, T. L., Lee, H.-Y., Hu, M., Liu, J.-L., Jasti, S. L., Liu, T.-J., Conrad, C. A., Yung, W. K. A. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann. Neurol. 53: 109-117, 2003. [PubMed: 12509854, related citations] [Full Text]
Greenberg, J. I., Shields, D. J., Barillas, S. G., Acevedo, L. M., Murphy, E., Huang, J., Scheppke, L., Stockmann, C., Johnson, R. S., Angle, N., Cheresh, D. A. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456: 809-813, 2008. Note: Erratum: Nature 457: 1168 only, 2009. [PubMed: 18997771, images, related citations] [Full Text]
Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Jung, S., Chimenti, S., Landsman, L., Abramovitch, R., Keshet, E. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124: 175-189, 2006. Note: Erratum: Cell 126: 811 only, 2006. [PubMed: 16413490, related citations] [Full Text]
Hamosh, A. Personal Communication. Baltimore, Md. May 14, 2018.
Helmlinger, G., Endo, M., Ferrara, N., Hlatky, L., Jain, R. K. Formation of endothelial cell networks. Nature 405: 139-141, 2000. [PubMed: 10821260, related citations] [Full Text]
Hofman, P., van Blijswijk, B. C., Gaillard, P. J., Vrensen, G. F. J. M., Schlingemann, R. O. Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion. Arch. Ophthal. 119: 861-866, 2001. [PubMed: 11405837, related citations] [Full Text]
Holash, J., Maisonpierre, P. C., Compton, D., Boland, P., Alexander, C. R., Zagzag, D., Yancopoulos, G. D., Wiegand, S. J. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284: 1994-1998, 1999. [PubMed: 10373119, related citations] [Full Text]
Howell, W. M., Ali, S., Rose-Zerilli, M. J., Ye, S. VEGF polymorphisms and severity of atherosclerosis. J. Med. Genet. 42: 485-490, 2005. [PubMed: 15937083, related citations] [Full Text]
Ishida, S., Usui, T., Yamashiro, K., Kaji, Y., Ahmed, E., Carrasquillo, K. G., Amano, S., Hida, T., Oguchi, Y., Adamis, A. P. VEGF-164 is proinflammatory in the diabetic retina. Invest. Ophthal. Vis. Sci. 44: 2155-2162, 2003. [PubMed: 12714656, related citations] [Full Text]
Jin, K., Zhu, Y., Sun, Y., Mao, X. O., Xie, L., Greenberg, D. A. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Nat. Acad. Sci. 99: 11946-11950, 2002. [PubMed: 12181492, images, related citations] [Full Text]
Klein, M., Vignaud, J.-M., Hennequin, V., Toussaint, B., Bresler, L., Plenat, F., Leclere, J., Duprez, A., Weryha, G. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J. Clin. Endocr. Metab. 86: 656-658, 2001. [PubMed: 11158026, related citations] [Full Text]
Kleinman, M. E., Yamada, K., Takeda, A., Chandrasekaran, V., Nozaki, M., Baffi, J. Z., Albuquerque, R. J. C., Yamasaki, S., Itaya, M., Pan, Y., Appukuttan, B., Gibbs, D., and 10 others. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452: 591-597, 2008. [PubMed: 18368052, images, related citations] [Full Text]
Kokki, E., Karttunen, T., Olsson, V., Kinnunen, K., Yla-Herttuala, S. Human vascular endothelial growth factor A-165 expression induces the mouse model of neovascular age-related macular degeneration. Genes 9: 438, 2018. Note: Electronic Article. [PubMed: 30200369, related citations] [Full Text]
Krzystolik, M. G., Afshari, M. A., Adamis, A. P., Gaudreault, J., Gragoudas, E. S., Michaud, N. A., Li, W., Connolly, E., O'Neill, C. A., Miller, J. W. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthal. 120: 338-346, 2002. [PubMed: 11879138, related citations] [Full Text]
Lambrechts, D., Devriendt, K., Driscoll, D. A., Goldmuntz, E., Gewillig, M., Vlietinck, R., Collen, D., Carmeliet, P. Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study. (Letter) J. Med. Genet. 42: 519-522, 2005. [PubMed: 15937089, related citations] [Full Text]
Lambrechts, D., Poesen, K., Fernandez-Santiago, R., Al-Chalabi, A., Del Bo, R., Van Vught, P. W. J., Khan, S., Marklund, S. L., Brockington, A., van Marion, I., Anneser, J., Shaw, C., and 12 others. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype. J. Med. Genet. 46: 840-846, 2009. [PubMed: 18413368, related citations] [Full Text]
Lambrechts, D., Storkebaum, E., Morimoto, M., Del-Favero, J., Desmet, F., Marklund, S. L., Wyns, S., Thijs, V., Andersson, J., van Marion, I., Al-Chalabi, A., Bornes, S., and 22 others. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genet. 34: 383-394, 2003. [PubMed: 12847526, related citations] [Full Text]
LeCouter, J., Moritz, D. R., Li, B., Phillips, G. L., Liang, X. H., Gerber, H.-P., Hillan, K. J., Ferrara, N. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299: 890-893, 2003. [PubMed: 12574630, related citations] [Full Text]
Lee, C. G., Link, H., Baluk, P., Homer, R. J., Chapoval, S., Bhandari, V., Kang, M. J., Cohn, L., Kim, Y. K., McDonald, D. M., Elias, J. A. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nature Med. 10: 1095-1103, 2004. [PubMed: 15378055, images, related citations] [Full Text]
Leng, R., Zha, L., Tang, L. MiR-718 represses VEGF and inhibits ovarian cancer cell progression. FEBS Lett. 588: 2078-2086, 2014. [PubMed: 24815691, related citations] [Full Text]
Leung, D. W., Cachianes, G., Kuang, W.-J., Goeddel, D. V., Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306-1309, 1989. [PubMed: 2479986, related citations] [Full Text]
Mattei, M.-G., Borg, J.-P., Rosnet, O., Marme, D., Birnbaum, D. Assignment of vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) genes to human chromosome 6p12-p21 and 14q24-q31 regions, respectively. Genomics 32: 168-169, 1996. [PubMed: 8786112, related citations] [Full Text]
Maynard, S. E., Min, J.-Y., Merchan, J., Lim, K.-H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., Epstein, F. H., Sukhatme, V. P., Karumanchi, S. A. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111: 649-658, 2003. [PubMed: 12618519, images, related citations] [Full Text]
Millauer, B., Shawver, L. K., Plate, K. H., Risau, W., Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576-579, 1994. [PubMed: 8107827, related citations] [Full Text]
Miralles, G. D., O'Fallon, J. R., Talley, N. J. Plasma-cell dyscrasia with polyneuropathy: the spectrum of POEMS syndrome. New Eng. J. Med. 327: 1919-1923, 1992. [PubMed: 1333569, related citations] [Full Text]
Mueller, M. D., Vigne, J.-L., Minchenko, A., Lebovic, D. I., Leitman, D. C., Taylor, R. N. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc. Nat. Acad. Sci. 97: 10972-10977, 2000. [PubMed: 10995484, images, related citations] [Full Text]
Nakanishi, T., Sobue, I., Toyokura, Y., Nishitani, H., Kuroiwa, Y., Satoyoshi, E., Tsubaki, T., Igata, A., Ozaki, Y. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 34: 712-720, 1984. [PubMed: 6539431, related citations] [Full Text]
Niimi, H., Arimura, K., Jonosono, M., Hashiguchi, T., Kawabata, M., Osame, M., Kitajima, I. VEGF is causative for pulmonary hypertension in a patient with Crow-Fukase (POEMS) syndrome. Intern. Med. 39: 1101-1104, 2000. [PubMed: 11197800, related citations] [Full Text]
Nobile-Orazio, E., Terenghi, F., Giannotta, C., Gallia, F., Nozza, A. Serum VEGF levels in POEMS syndrome and in immune-mediated neuropathies. Neurology 72: 1024-1026, 2009. [PubMed: 19289745, related citations] [Full Text]
Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444: 1032-1037, 2006. [PubMed: 17183313, related citations] [Full Text]
Nozaki, M., Sakurai, E., Raisler, B. J., Baffi, J. Z., Witta, J., Ogura, Y., Brekken, R. A., Sage, E. H., Ambati, B. K., Ambati, J. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J. Clin. Invest. 116: 422-429, 2006. [PubMed: 16453023, images, related citations] [Full Text]
Ogata, N., Nishikawa, M., Nishimura, T., Mitsuma, Y., Matsumura, M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am. J. Ophthal. 134: 348-353, 2002. [PubMed: 12208245, related citations] [Full Text]
Onesto, C., Berra, E., Grepin, R., Pages, G. Poly(A)-binding protein-interacting protein 2, a strong regulator of vascular endothelial growth factor mRNA. J. Biol. Chem. 279: 34217-34226, 2004. [PubMed: 15175342, related citations] [Full Text]
Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., Van Dorpe, J., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., and 20 others. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genet. 28: 131-138, 2001. [PubMed: 11381259, related citations] [Full Text]
Poltorak, Z., Cohen, T., Sivan, R., Kandelis, Y., Spira, G., Vlodavsky, I., Keshet, E., Neufeld, G. VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J. Biol. Chem. 272: 7151-7158, 1997. [PubMed: 9054410, related citations] [Full Text]
Poulaki, V., Mitsiades, C. S., McMullan, C., Sykoutri, D., Fanourakis, G., Kotoula, V., Tseleni-Balafouta, S., Koutras, D. A., Mitsiades, N. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas. J. Clin. Endocr. Metab. 88: 5392-5398, 2003. [PubMed: 14602779, related citations] [Full Text]
Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., Anand-Apte, B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med. 9: 407-415, 2003. [PubMed: 12652295, related citations] [Full Text]
Rao, S., Chun, C., Fan, J., Kofron, J. M., Yang, M. B., Hegde, R. S., Ferrara, N., Copenhagen, D. R., Lang, R. A. A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature 494: 243-246, 2013. [PubMed: 23334418, images, related citations] [Full Text]
Ray, P. S., Jia, J., Yao, P., Majumder, M., Hatzoglou, M., Fox, P. L. A stress-responsive RNA switch regulates VEGFA expression. Nature 457: 915-919, 2009. [PubMed: 19098893, images, related citations] [Full Text]
Ruhrberg, C., Gerhardt, H., Golding, M., Watson, R., Ioannidou, S., Fujisawa, H., Betscholtz, C., Shima, D. T. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16: 2684-2698, 2002. [PubMed: 12381667, images, related citations] [Full Text]
Shimpo, S. Solitary myeloma causing polyneuritis and endocrine disorders. Nippon Rinsho 26: 2444-2456, 1968. [PubMed: 5752014, related citations]
Simo, R., Lecube, A., Segura, R. M., Garcia Arumi, J., Hernandez, C. Free insulin growth factor-1 and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Am. J. Ophthal. 134: 376-382, 2002. [PubMed: 12208249, related citations] [Full Text]
Smith, C. L., Birdsey, G. M., Anthony, S., Arrigoni, F. I., Leiper, J. M., Vallance, P. Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochem. Biophys. Res. Commun. 308: 984-989, 2003. [PubMed: 12927816, related citations] [Full Text]
Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92: 735-745, 1998. [PubMed: 9529250, related citations] [Full Text]
Sone, H., Kawakami, Y., Sakauchi, M., Nakamura, Y., Takahashi, A., Shimano, H., Okuda, Y., Segawa, T., Suzuki, H., Yamada, N. Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis and ameliorates established disease in mice. Biochem. Biophys. Res. Commun. 281: 562-568, 2001. [PubMed: 11181084, related citations] [Full Text]
Springer, M. L., Chen, A. S., Kraft, P. E., Bednarski, M., Blau, H. M. VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Molec. Cell 2: 549-558, 1998. [PubMed: 9844628, related citations] [Full Text]
Stalmans, I., Lambrechts, D., De Smet, F., Jansen, S., Wang, J., Maity, S., Kneer, P., von der Ohe, M., Swillen, A., Maes, C., Gewillig, M., Molin, D. G. M., and 20 others. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nature Med. 9: 173-182, 2003. [PubMed: 12539040, related citations] [Full Text]
Stockmann, C., Doedens, A., Weidemann, A., Zhang, N., Takeda, N., Greenberg, J. I., Cheresh, D. A., Johnson, R. S. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456: 814-818, 2008. [PubMed: 18997773, images, related citations] [Full Text]
Tam, B. Y. Y., Wei, K., Rudge, J. S., Hoffman, J., Holash, J., Park, S., Yuan, J., Hefner, C., Chartier, C., Lee, J.-S., Jiang, S., Nayak, N. R., and 11 others. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nature Med. 12: 793-800, 2006. Note: Erratum: Nature Med. 15: 462 only, 2009. [PubMed: 16799557, related citations] [Full Text]
Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. N., Yancopoulos, G. D., McDonald, D. M. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286: 2511-2514, 1999. [PubMed: 10617467, related citations] [Full Text]
Tischer, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J. C., Abraham, J. A. The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266: 11947-11954, 1991. [PubMed: 1711045, related citations]
Van Vught, P. W. J., Sutedja, N. A., Veldink, J. H., Koeleman, B. P. C., Groeneveld, G. J., Wijmenga, C., Uitdehaag, B. M. J., de Jong, J. M. B. V., Baas, F., Wokke, J. H. J., Van den Berg, L. H. Lack of association between VEGF polymorphisms and ALS in a Dutch population. Neurology 65: 1643-1645, 2005. [PubMed: 16301496, related citations] [Full Text]
Vincenti, V., Cassano, C., Rocchi, M., Persico, M. G. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93: 1493-1495, 1996. [PubMed: 8608615, related citations] [Full Text]
Watanabe, D., Suzuma, K., Suzuma, I., Ohashi, H., Ojima, T., Kurimoto, M., Murakami, T., Kimura, T., Takagi, H. Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am. J. Ophthal. 139: 476-481, 2005. [PubMed: 15767056, related citations] [Full Text]
Watanabe, O., Maruyama, I., Arimura, K., Kitajima, I., Arimura, H., Hanatani, M., Matsuo, K., Arisato, T., Osame, M. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome. Muscle Nerve 21: 1390-1397, 1998. [PubMed: 9771661, related citations] [Full Text]
Wei, M.-H., Popescu, N. C., Lerman, M. I., Merrill, M. J., Zimonjic, D. B. Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6p12. Hum. Genet. 97: 794-797, 1996. [PubMed: 8641698, related citations]
Wong, A. K., Alfert, M., Castrillon, D. H., Shen, Q., Holash, J., Yancopoulos, G. D., Chin, L. Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome. Proc. Nat. Acad. Sci. 98: 7481-7486, 2001. [PubMed: 11404464, images, related citations] [Full Text]
Wulff, C., Wilson, H., Largue, P., Duncan, W. C., Armstrong, D. G., Fraser, H. M. Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, Tie-2, and vascular endothelial growth factor messenger ribonucleic acid. J. Clin. Endocr. Metab. 85: 4302-4309, 2000. [PubMed: 11095472, related citations] [Full Text]
Yao, Y.-G., Duh, E. J. VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis. Biochem. Biophys. Res. Commun. 321: 648-656, 2004. [PubMed: 15358155, related citations] [Full Text]
Ylikorkala, A., Rossi, D. J., Korsisaari, N., Luukko, K., Alitalo, K., Henkemeyer, M., Makela, T. P. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293: 1323-1326, 2001. [PubMed: 11509733, related citations] [Full Text]
Zarbock, R., Hendig, D., Szliska, C., Kleesiek, K., Gotting, C. Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum. Hum. Molec. Genet. 18: 3344-3351, 2009. [PubMed: 19483196, related citations] [Full Text]

Contributors:

Bao Lige - updated : 05/30/2019

Ada Hamosh - updated : 10/10/2014
Patricia A. Hartz - updated : 8/26/2014
Ada Hamosh - updated : 2/26/2013
Ada Hamosh - updated : 4/24/2012
Ada Hamosh - updated : 11/29/2011
Cassandra L. Kniffin - updated : 3/17/2011
George E. Tiller - updated : 7/7/2010
Cassandra L. Kniffin - updated : 6/14/2010
Paul J. Converse - updated : 5/25/2010
Cassandra L. Kniffin - updated : 6/29/2009
Ada Hamosh - updated : 6/18/2009
Cassandra L. Kniffin - updated : 5/29/2009
Matthew B. Gross - updated : 5/14/2009
Ada Hamosh - updated : 3/9/2009
Marla J. F. O'Neill - updated : 2/12/2009
Ada Hamosh - updated : 1/29/2009
Ada Hamosh - updated : 4/15/2008
Ada Hamosh - updated : 3/18/2008
Jane Kelly - updated : 12/12/2007
Cassandra L. Kniffin -updated : 10/2/2007
Cassandra L. Kniffin - updated : 9/14/2007
Ada Hamosh - updated : 4/20/2007
Cassandra L. Kniffin - updated : 2/15/2007
Patricia A. Hartz - updated : 12/18/2006
Patricia A. Hartz - updated : 8/10/2006
Marla J. F. O'Neill - updated : 7/10/2006
Paul J. Converse - updated : 9/2/2005
Cassandra L. Kniffin - updated : 7/27/2005
Marla J. F. O'Neill - updated : 7/21/2005
Victor A. McKusick - updated : 7/5/2005
Jane Kelly - updated : 7/1/2005
John A. Phillips, III - updated : 4/20/2005
Marla J. F. O'Neill - updated : 2/18/2005
Patricia A. Hartz - updated : 2/4/2005
Victor A. McKusick - updated : 8/20/2004
Jane Kelly - updated : 7/28/2004
Ada Hamosh - updated : 6/11/2004
Marla J. F. O'Neill - updated : 3/12/2004
Jane Kelly - updated : 8/22/2003
Ada Hamosh - updated : 7/24/2003
Victor A. McKusick - updated : 7/7/2003
Ada Hamosh - updated : 6/17/2003
Cassandra L. Kniffin - updated : 5/15/2003
Patricia A. Hartz - updated : 4/21/2003
Ada Hamosh - updated : 4/15/2003
Jane Kelly - updated : 4/9/2003
Jane Kelly - updated : 4/7/2003
Ada Hamosh - updated : 4/1/2003
Jane Kelly - updated : 3/27/2003
Ada Hamosh - updated : 2/27/2003
Ada Hamosh - updated : 2/21/2003
John A. Phillips, III - updated : 12/16/2002
Jane Kelly - updated : 11/5/2002
Victor A. McKusick - updated : 10/11/2002
John A. Phillips, III - updated : 7/30/2002
Ada Hamosh - updated : 7/9/2002
Jane Kelly - updated : 7/2/2002
Jane Kelly - updated : 4/3/2002
Ada Hamosh - updated : 8/27/2001
John A. Phillips, III - updated : 8/17/2001
Victor A. McKusick - updated : 7/18/2001
John A. Phillips, III - updated : 7/6/2001
Victor A. McKusick - updated : 6/19/2001
Victor A. McKusick - updated : 6/1/2001
Ada Hamosh - updated : 5/2/2001
Ada Hamosh - updated : 4/20/2001
Victor A. McKusick - updated : 11/29/2000
Victor A. McKusick - updated : 10/26/2000
Paul J. Converse - updated : 6/8/2000
Ada Hamosh - updated : 5/10/2000
Ada Hamosh - updated : 12/27/1999
Ada Hamosh - updated : 6/23/1999
Ada Hamosh - updated : 6/17/1999
Stylianos E. Antonarakis - updated : 2/9/1999
Stylianos E. Antonarakis - updated : 9/30/1998
Stylianos E. Antonarakis - updated : 5/22/1998
Moyra Smith - Updated : 5/10/1996

Creation Date:

Victor A. McKusick : 9/11/1991

Edit History:

mgross : 05/30/2019

carol : 05/15/2018
carol : 11/13/2017
carol : 08/04/2016
alopez : 08/31/2015
alopez : 10/10/2014
mgross : 8/26/2014
carol : 8/21/2014
mcolton : 8/21/2014
carol : 2/17/2014
carol : 2/3/2014
alopez : 3/4/2013
terry : 2/26/2013
terry : 5/10/2012
alopez : 4/25/2012
terry : 4/24/2012
alopez : 12/1/2011
terry : 11/29/2011
wwang : 6/13/2011
terry : 4/26/2011
wwang : 3/28/2011
ckniffin : 3/17/2011
ckniffin : 3/17/2011
wwang : 7/20/2010
wwang : 7/7/2010
terry : 7/7/2010
wwang : 6/18/2010
ckniffin : 6/14/2010
wwang : 5/25/2010
wwang : 3/1/2010
wwang : 7/29/2009
ckniffin : 6/29/2009
alopez : 6/24/2009
terry : 6/18/2009
wwang : 6/3/2009
ckniffin : 5/29/2009
wwang : 5/29/2009
mgross : 5/14/2009
mgross : 4/29/2009
alopez : 3/11/2009
alopez : 3/10/2009
terry : 3/9/2009
carol : 2/19/2009
carol : 2/13/2009
carol : 2/12/2009
alopez : 2/6/2009
terry : 1/29/2009
carol : 9/24/2008
alopez : 5/16/2008
alopez : 5/16/2008
terry : 4/15/2008
alopez : 3/26/2008
terry : 3/18/2008
carol : 12/12/2007
wwang : 10/8/2007
ckniffin : 10/2/2007
wwang : 9/21/2007
ckniffin : 9/14/2007
alopez : 4/24/2007
terry : 4/20/2007
wwang : 2/19/2007
ckniffin : 2/15/2007
wwang : 12/20/2006
terry : 12/18/2006
wwang : 11/8/2006
mgross : 8/10/2006
terry : 8/10/2006
wwang : 7/11/2006
terry : 7/10/2006
mgross : 9/2/2005
carol : 8/12/2005
carol : 8/12/2005
wwang : 8/9/2005
ckniffin : 7/27/2005
ckniffin : 7/27/2005
wwang : 7/25/2005
terry : 7/21/2005
wwang : 7/6/2005
terry : 7/5/2005
alopez : 7/1/2005
alopez : 4/20/2005
terry : 3/11/2005
wwang : 2/23/2005
terry : 2/18/2005
mgross : 2/4/2005
terry : 11/4/2004
tkritzer : 8/23/2004
terry : 8/20/2004
tkritzer : 7/28/2004
alopez : 6/15/2004
alopez : 6/15/2004
terry : 6/11/2004
carol : 4/27/2004
tkritzer : 3/25/2004
tkritzer : 3/12/2004
alopez : 9/2/2003
mgross : 8/22/2003
alopez : 7/28/2003
carol : 7/24/2003
terry : 7/24/2003
alopez : 7/10/2003
terry : 7/7/2003
alopez : 6/18/2003
terry : 6/17/2003
cwells : 5/20/2003
ckniffin : 5/15/2003
cwells : 4/24/2003
terry : 4/21/2003
alopez : 4/17/2003
terry : 4/15/2003
cwells : 4/9/2003
cwells : 4/7/2003
alopez : 4/3/2003
terry : 4/1/2003
cwells : 3/27/2003
alopez : 3/4/2003
terry : 2/27/2003
alopez : 2/25/2003
terry : 2/21/2003
alopez : 12/16/2002
carol : 11/5/2002
tkritzer : 10/28/2002
tkritzer : 10/16/2002
terry : 10/11/2002
tkritzer : 7/31/2002
tkritzer : 7/30/2002
alopez : 7/10/2002
terry : 7/9/2002
mgross : 7/2/2002
terry : 6/26/2002
mgross : 4/3/2002
mgross : 4/3/2002
carol : 10/24/2001
cwells : 9/4/2001
cwells : 8/29/2001
terry : 8/27/2001
mgross : 8/17/2001
mcapotos : 8/9/2001
mcapotos : 8/9/2001
mcapotos : 7/27/2001
terry : 7/18/2001
alopez : 7/6/2001
mcapotos : 6/25/2001
mcapotos : 6/19/2001
terry : 6/19/2001
mcapotos : 6/4/2001
terry : 6/1/2001
alopez : 5/7/2001
terry : 5/2/2001
alopez : 4/30/2001
terry : 4/20/2001
mcapotos : 12/18/2000
terry : 11/29/2000
mcapotos : 11/8/2000
mcapotos : 11/1/2000
terry : 10/26/2000
carol : 6/8/2000
alopez : 5/10/2000
carol : 5/10/2000
alopez : 12/27/1999
alopez : 6/23/1999
alopez : 6/17/1999
mgross : 4/7/1999
mgross : 2/9/1999
carol : 9/30/1998
carol : 5/22/1998
jenny : 4/21/1997
mark : 10/21/1996
carol : 8/23/1996
carol : 5/15/1996
carol : 5/15/1996
carol : 5/10/1996
mark : 4/4/1996
terry : 4/4/1996
mark : 3/13/1996
mark : 3/11/1996
terry : 3/7/1996
mark : 11/14/1995
supermim : 3/16/1992
carol : 9/11/1991

* 192240

VASCULAR ENDOTHELIAL GROWTH FACTOR A; VEGFA

Alternative titles; symbols

VEGF

HGNC Approved Gene Symbol: VEGFA

Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:43,770,211-43,786,487 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
6p21.1	{Microvascular complications of diabetes 1}	603933		3

TEXT

Description

Vascular endothelial growth factor is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo (summary by Leung et al., 1989).

Cloning and Expression

By RT-PCR on carcinoma cell lines, Poltorak et al. (1997) identified a VEGF isoform predicted to contain 145 amino acids and to lack exon 7, which they termed VEGF145.

Gene Structure

Gene Function

Leung et al. (1989) demonstrated that culture media conditioned by human embryonic kidney cells expressing either bovine or human VEGF cDNA promoted proliferation of capillary endothelial cells.

POEMS Syndrome

Biochemical Features

Mapping

Molecular Genetics

Role in Diabetic Retinopathy

Possible Role in Amyotrophic Lateral Sclerosis

Possible Role in Pseudoxanthoma Elasticum-Related Retinopathy

Role in Other Disorders

Del Bo et al. (2005) presented evidence suggesting that the VEGF -2578A/A genotype confers an increased risk for the development of Alzheimer disease (AD; see 104300).

Animal Model

ALLELIC VARIANTS 2 Selected Examples):

.0001 MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 1

VEGFA, -634G-C, ({dbSNP rs2010963})
SNP: rs2010963, gnomAD: rs2010963, ClinVar: RCV000013007, RCV001618210

.0002 RECLASSIFIED - VASCULAR ENDOTHELIAL GROWTH FACTOR A POLYMORPHISM

VEGFA, -2578C-A, ({dbSNP rs699947})
SNP: rs699947, gnomAD: rs699947, ClinVar: RCV000013008

Atherosclerosis, Susceptibility to

Alzheimer Diseae, Susceptibility to

Amyotrophic Lateral Sclerosis in Males, Susceptibility to

Lambrechts et al. (2009) performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing.

REFERENCES

Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., Cheresh, D. A. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301: 94-96, 2003. [PubMed: 12843393] [Full Text: https://doi.org/10.1126/science.1082015]
Arany, Z., Foo, S.-Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H., Rosenzweig, A., Spiegelman, B. M. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1-alpha. Nature 451: 1008-1012, 2008. [PubMed: 18288196] [Full Text: https://doi.org/10.1038/nature06613]
Argaw, A. T., Gurfein, B. T., Zhang, Y., Zameer, A., John, G. R. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc. Nat. Acad. Sci. 106: 1977-1982, 2009. [PubMed: 19174516] [Full Text: https://doi.org/10.1073/pnas.0808698106]
Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plaisance, S., De Mol, M., Bono, F., Kliche, S., Fellbrich, G., and 16 others. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Med. 9: 936-943, 2003. [PubMed: 12796773] [Full Text: https://doi.org/10.1038/nm884]
Awata, T., Inoue, K., Kurihara, S., Ohkubo, T., Watanabe, M., Inukai, K., Inoue, I., Katayama, S. A common polymorphism in the 5-prime-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51: 1635-1639, 2002. [PubMed: 11978667] [Full Text: https://doi.org/10.2337/diabetes.51.5.1635]
Azzouz, M., Ralph, G. S., Storkebaum, E., Walmsley, L. E., Mitrophanous, K. A., Kingsman, S. M., Carmeliet, P., Mazarakis, N. D. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429: 413-417, 2004. [PubMed: 15164063] [Full Text: https://doi.org/10.1038/nature02544]
Bainbridge, J. W. B., Jia, H., Bagherzadeh, A., Selwood, D., Ali, R. R., Zachary, I. A peptide encoded by exon 6 of VEGF (EG3306) inhibits VEGF-induced angiogenesis in vitro and ischaemic retinal neovascularisation in vivo. Biochem. Biophys. Res. Commun. 302: 793-799, 2003. [PubMed: 12646239] [Full Text: https://doi.org/10.1016/s0006-291x(03)00222-5]
Bardwick, P. A., Zvaifler, N. J., Gill, G. N., Newman, D., Greenway, G. D., Resnick, D. L. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine 59: 311-322, 1980. [PubMed: 6248720] [Full Text: https://doi.org/10.1097/00005792-198007000-00006]
Basu, A., Hoerning, A., Datta, D., Edelbauer, M., Stack, M. P., Calzadilla, K., Pal, S., Briscoe, D. M. Cutting edge: vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production. J. Immunol. 184: 545-549, 2010. [PubMed: 20008289] [Full Text: https://doi.org/10.4049/jimmunol.0900397]
Basu, S., Nagy, J. A., Pal, S., Vasile, E., Eckelhoefer, I. A., Bliss, V. S., Manseau, E. J., Dasgupta, P. S., Dvorak, H. F., Mukhopadhyay, D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nature Med. 7: 569-574, 2001. [PubMed: 11329058] [Full Text: https://doi.org/10.1038/87895]
Beck, B., Driessens, G., Goossens, S., Youssef, K. K., Kuchnio, A., Caauwe, A., Sotiropoulou, P. A., Loges, S., Lapouge, G., Candi, A., Mascre, G., Drogat, B., Dekoninck, S., Haigh, J. J., Carmeliet, P., Blanpain, C. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478: 399-403, 2011. [PubMed: 22012397] [Full Text: https://doi.org/10.1038/nature10525]
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484: 110-114, 2012. [PubMed: 22426001] [Full Text: https://doi.org/10.1038/nature10908]
Bock, F., Onderka, J., Dietrich, T., Bachmann, B., Kruse, F. E., Paschke, M., Zahn, G., Cursiefen, C. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest. Ophthal. Vis. Sci. 48: 2545-2552, 2007. [PubMed: 17525183] [Full Text: https://doi.org/10.1167/iovs.06-0570]
Bostrom, J., Yu, S.-F., Kan, D., Appleton, B. A., Lee, C. V., Billeci, K., Man, W., Peale, F., Ross, S., Wiesmann, C., Fuh, G. Variants of the antibody Herceptin that interact with HER2 and VEGF at the antigen binding site. Science 323: 1610-1614, 2009. [PubMed: 19299620] [Full Text: https://doi.org/10.1126/science.1165480]
Cao, L., Jiao, X., Zuzga, D. S., Liu, Y., Fong, D. M., Young, D., During, M. J. VEGF links hippocampal activity with neurogenesis, learning and memory. Nature Genet. 36: 827-835, 2004. [PubMed: 15258583] [Full Text: https://doi.org/10.1038/ng1395]
Carmeliet, P., Ferreira, V., Breler, G., Pollefeyt, S., Kleckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declercq, C., Pawling, J., Moons, L., Collen, D., Risau, W., Nagy, A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435-439, 1996. [PubMed: 8602241] [Full Text: https://doi.org/10.1038/380435a0]
Carpenter, T., Schomberg, S., Steudel, W., Ozimek, J., Colvin, K., Stenmark, K., Ivy, D. D. Endothelin B receptor deficiency predisposes to pulmonary edema formation via increased lung vascular endothelial cell growth factor expression. Circ. Res. 93: 456-463, 2003. [PubMed: 12919946] [Full Text: https://doi.org/10.1161/01.RES.0000090994.15442.42]
Chen, W., Saeed, M., Mao, H., Siddique, N., Dellefave, L., Hung, W.-Y., Deng, H.-X., Sufit, R. L., Heller, S. L., Haines, J. L., Pericak-Vance, M., Siddique, T. Lack of association of VEGF promoter polymorphisms with sporadic ALS. Neurology 67: 508-510, 2006. [PubMed: 16894118] [Full Text: https://doi.org/10.1212/01.wnl.0000227926.42370.04]
Colegio, O. R., Chu, N.-Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., Cyrus, N., Brokowski, C. E., Eisenbarth, S. C., Phillips, G. M., Cline, G. W., Phillips, A. J., Medzhitov, R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513: 559-563, 2014. [PubMed: 25043024] [Full Text: https://doi.org/10.1038/nature13490]
Crow, R. S. Peripheral neuritis in myelomatosis. Brit. Med. J. 2: 802-804, 1956. [PubMed: 13364332] [Full Text: https://doi.org/10.1136/bmj.2.4996.802]
Dantz, D., Bewersdorf, J., Fruehwald-Schultes, B., Kern, W., Jelkmann, W., Born, J., Fehm, H. L., Peters, A. Vascular endothelial growth factor: a novel endocrine defensive response to hypoglycemia. J. Clin. Endocr. Metab. 87: 835-840, 2002. [PubMed: 11836329] [Full Text: https://doi.org/10.1210/jcem.87.2.8215]
de Fraipont, F., El Atifi, M., Gicquel, C., Bertagna, X., Chambaz, E. M., Feige, J. J. Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. J. Clin. Endocr. Metab. 85: 4734-4741, 2000. [PubMed: 11134136] [Full Text: https://doi.org/10.1210/jcem.85.12.7012]
Del Bo, R., Scarlato, M., Ghezzi, S., Martinelli Boneschi, F., Fenoglio, C., Galbiati, S., Virgilio, R., Galimberti, D., Galimberti, G., Crimi, M., Ferrarese, C., Scarpini, E., Bresolin, N., Comi, G. P. Vascular endothelial growth factor gene variability is associated with increased risk for AD. Ann. Neurol. 57: 373-380, 2005. [PubMed: 15732116] [Full Text: https://doi.org/10.1002/ana.20390]
Diduszyn, J. M., Quillen, D. A., Cantore, W. A., Gardner, T. W. Optic disk drusen, peripapillary choroidal neovascularization, and POEMS syndrome. Am. J. Ophthal. 133: 275-276, 2002. [PubMed: 11812439] [Full Text: https://doi.org/10.1016/s0002-9394(01)01270-3]
Dupont, S. A., Dispenzieri, A., Mauermann, M. L., Rabenstein, A. A., Brown, R. D., Jr. Cerebral infarction in POEMS syndrome: incidence, risk factors, and imaging characteristics. Neurology 73: 1308-1312, 2009. [PubMed: 19841383] [Full Text: https://doi.org/10.1212/WNL.0b013e3181bd136b]
Fernandez-Santiago, R., Sharma, M., Mueller, J. C., Gohlke, H., Illig, T., Anneser, J., Munch, C., Ludolph, A., Kamm, C., Gasser, T. Possible gender-dependent association of vascular endothelial growth factor (VEGF) gene and ALS. Neurology 66: 1929-1931, 2006. [PubMed: 16801663] [Full Text: https://doi.org/10.1212/01.wnl.0000219756.71928.25]
Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, K. S., Powell-Braxton, L., Hillan, K. J., Moore, M. W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439-442, 1996. [PubMed: 8602242] [Full Text: https://doi.org/10.1038/380439a0]
Ferrara, N., Henzel, W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161: 851-858, 1989. [PubMed: 2735925] [Full Text: https://doi.org/10.1016/0006-291x(89)92678-8]
Ferrari, G., Pintucci, G., Seghezzi, G., Hyman, K., Galloway, A. C., Mignatti, P. VEGF, a prosurvival factor, acts in concert with TGF-beta-1 to induce endothelial cell apoptosis. Proc. Nat. Acad. Sci. 103: 17260-17265, 2006. [PubMed: 17088559] [Full Text: https://doi.org/10.1073/pnas.0605556103]
Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1: 27-31, 1995. [PubMed: 7584949] [Full Text: https://doi.org/10.1038/nm0195-27]
Fukumura, D., Xavier, R., Sugiura, T., Chen, Y., Park, E.-C., Lu, N., Selig, M., Nielsen, G., Taksir, T., Jain, R. K., Seed, B. Tumor induction of VEGF promoter activity in stromal cells. Cell 94: 715-725, 1998. [PubMed: 9753319] [Full Text: https://doi.org/10.1016/s0092-8674(00)81731-6]
Funatsu, H., Yamashita, H., Noma, H., Mimura, T., Yamashita, T., Hori, S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am. J. Ophthal. 133: 70-77, 2002. [PubMed: 11755841] [Full Text: https://doi.org/10.1016/s0002-9394(01)01269-7]
Gerber, H.-P., Malik, A. K., Solar, G. P., Sherman, D., Liang, X. H., Meng, G., Hong, K., Marsters, J. C., Ferrara, N. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417: 954-958, 2002. [PubMed: 12087404] [Full Text: https://doi.org/10.1038/nature00821]
Gerber, H.-P., Vu, T. H., Ryan, A. M., Kowalski, J., Werb, Z., Ferrara, N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5: 623-628, 1999. [PubMed: 10371499] [Full Text: https://doi.org/10.1038/9467]
Geva, E., Ginzinger, D. G., Zaloudek, C. J., Moore, D. H., Byrne, A., Jaffe, R. B. Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J. Clin. Endocr. Metab. 87: 4213-4224, 2002. [PubMed: 12213874] [Full Text: https://doi.org/10.1210/jc.2002-020195]
Giordano, F. J., Gerber, H.-P., Williams, S.-P., VanBruggen, N., Bunting, S., Ruiz-Lozano, P., Gu, Y., Nath, A. K., Huang, Y., Hickey, R., Dalton, N., Peterson, K. L., Ross, J., Jr., Chien, K. R., Ferrara, N. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc. Nat. Acad. Sci. 98: 5780-5785, 2001. [PubMed: 11331753] [Full Text: https://doi.org/10.1073/pnas.091415198]
Gogat, K., Le Gat, L., Van Den Berghe, L., Marchant, D., Kobetz, A., Gadin, S., Gasser, B., Quere, I., Abitbol, M., Menasche, M. VEGF and KDR gene expression during human embryonic and fetal eye development. Invest. Ophthal. Vis. Sci. 45: 7-14, 2004. [PubMed: 14691147] [Full Text: https://doi.org/10.1167/iovs.02-1096]
Golenia, A., Tomik, B., Zawislak, D., Wolkow, P., Dziubek, A., Sado, M., Szczudlik, A., Figlewicz, D. A., Slowik, A. Lack of association between VEGF gene polymorphisms and plasma VEGF levels and sporadic ALS. Neurology 75: 2035-2037, 2010. [PubMed: 21115961] [Full Text: https://doi.org/10.1212/WNL.0b013e3181ff9658]
Gomez-Manzano, C., Fueyo, J., Jiang, H., Glass, T. L., Lee, H.-Y., Hu, M., Liu, J.-L., Jasti, S. L., Liu, T.-J., Conrad, C. A., Yung, W. K. A. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann. Neurol. 53: 109-117, 2003. [PubMed: 12509854] [Full Text: https://doi.org/10.1002/ana.10396]
Greenberg, J. I., Shields, D. J., Barillas, S. G., Acevedo, L. M., Murphy, E., Huang, J., Scheppke, L., Stockmann, C., Johnson, R. S., Angle, N., Cheresh, D. A. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456: 809-813, 2008. Note: Erratum: Nature 457: 1168 only, 2009. [PubMed: 18997771] [Full Text: https://doi.org/10.1038/nature07424]
Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Jung, S., Chimenti, S., Landsman, L., Abramovitch, R., Keshet, E. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124: 175-189, 2006. Note: Erratum: Cell 126: 811 only, 2006. [PubMed: 16413490] [Full Text: https://doi.org/10.1016/j.cell.2005.10.036]
Hamosh, A. Personal Communication. Baltimore, Md. May 14, 2018.
Helmlinger, G., Endo, M., Ferrara, N., Hlatky, L., Jain, R. K. Formation of endothelial cell networks. Nature 405: 139-141, 2000. [PubMed: 10821260] [Full Text: https://doi.org/10.1038/35012132]
Hofman, P., van Blijswijk, B. C., Gaillard, P. J., Vrensen, G. F. J. M., Schlingemann, R. O. Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion. Arch. Ophthal. 119: 861-866, 2001. [PubMed: 11405837] [Full Text: https://doi.org/10.1001/archopht.119.6.861]
Holash, J., Maisonpierre, P. C., Compton, D., Boland, P., Alexander, C. R., Zagzag, D., Yancopoulos, G. D., Wiegand, S. J. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284: 1994-1998, 1999. [PubMed: 10373119] [Full Text: https://doi.org/10.1126/science.284.5422.1994]
Howell, W. M., Ali, S., Rose-Zerilli, M. J., Ye, S. VEGF polymorphisms and severity of atherosclerosis. J. Med. Genet. 42: 485-490, 2005. [PubMed: 15937083] [Full Text: https://doi.org/10.1136/jmg.2004.025734]
Ishida, S., Usui, T., Yamashiro, K., Kaji, Y., Ahmed, E., Carrasquillo, K. G., Amano, S., Hida, T., Oguchi, Y., Adamis, A. P. VEGF-164 is proinflammatory in the diabetic retina. Invest. Ophthal. Vis. Sci. 44: 2155-2162, 2003. [PubMed: 12714656] [Full Text: https://doi.org/10.1167/iovs.02-0807]
Jin, K., Zhu, Y., Sun, Y., Mao, X. O., Xie, L., Greenberg, D. A. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Nat. Acad. Sci. 99: 11946-11950, 2002. [PubMed: 12181492] [Full Text: https://doi.org/10.1073/pnas.182296499]
Klein, M., Vignaud, J.-M., Hennequin, V., Toussaint, B., Bresler, L., Plenat, F., Leclere, J., Duprez, A., Weryha, G. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J. Clin. Endocr. Metab. 86: 656-658, 2001. [PubMed: 11158026] [Full Text: https://doi.org/10.1210/jcem.86.2.7226]
Kleinman, M. E., Yamada, K., Takeda, A., Chandrasekaran, V., Nozaki, M., Baffi, J. Z., Albuquerque, R. J. C., Yamasaki, S., Itaya, M., Pan, Y., Appukuttan, B., Gibbs, D., and 10 others. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452: 591-597, 2008. [PubMed: 18368052] [Full Text: https://doi.org/10.1038/nature06765]
Kokki, E., Karttunen, T., Olsson, V., Kinnunen, K., Yla-Herttuala, S. Human vascular endothelial growth factor A-165 expression induces the mouse model of neovascular age-related macular degeneration. Genes 9: 438, 2018. Note: Electronic Article. [PubMed: 30200369] [Full Text: https://doi.org/10.3390/genes9090438]
Krzystolik, M. G., Afshari, M. A., Adamis, A. P., Gaudreault, J., Gragoudas, E. S., Michaud, N. A., Li, W., Connolly, E., O'Neill, C. A., Miller, J. W. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthal. 120: 338-346, 2002. [PubMed: 11879138] [Full Text: https://doi.org/10.1001/archopht.120.3.338]
Lambrechts, D., Devriendt, K., Driscoll, D. A., Goldmuntz, E., Gewillig, M., Vlietinck, R., Collen, D., Carmeliet, P. Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study. (Letter) J. Med. Genet. 42: 519-522, 2005. [PubMed: 15937089] [Full Text: https://doi.org/10.1136/jmg.2004.026443]
Lambrechts, D., Poesen, K., Fernandez-Santiago, R., Al-Chalabi, A., Del Bo, R., Van Vught, P. W. J., Khan, S., Marklund, S. L., Brockington, A., van Marion, I., Anneser, J., Shaw, C., and 12 others. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype. J. Med. Genet. 46: 840-846, 2009. [PubMed: 18413368] [Full Text: https://doi.org/10.1136/jmg.2008.058222]
Lambrechts, D., Storkebaum, E., Morimoto, M., Del-Favero, J., Desmet, F., Marklund, S. L., Wyns, S., Thijs, V., Andersson, J., van Marion, I., Al-Chalabi, A., Bornes, S., and 22 others. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genet. 34: 383-394, 2003. [PubMed: 12847526] [Full Text: https://doi.org/10.1038/ng1211]
LeCouter, J., Moritz, D. R., Li, B., Phillips, G. L., Liang, X. H., Gerber, H.-P., Hillan, K. J., Ferrara, N. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299: 890-893, 2003. [PubMed: 12574630] [Full Text: https://doi.org/10.1126/science.1079562]
Lee, C. G., Link, H., Baluk, P., Homer, R. J., Chapoval, S., Bhandari, V., Kang, M. J., Cohn, L., Kim, Y. K., McDonald, D. M., Elias, J. A. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nature Med. 10: 1095-1103, 2004. [PubMed: 15378055] [Full Text: https://doi.org/10.1038/nm1105]
Leng, R., Zha, L., Tang, L. MiR-718 represses VEGF and inhibits ovarian cancer cell progression. FEBS Lett. 588: 2078-2086, 2014. [PubMed: 24815691] [Full Text: https://doi.org/10.1016/j.febslet.2014.04.040]
Leung, D. W., Cachianes, G., Kuang, W.-J., Goeddel, D. V., Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306-1309, 1989. [PubMed: 2479986] [Full Text: https://doi.org/10.1126/science.2479986]
Mattei, M.-G., Borg, J.-P., Rosnet, O., Marme, D., Birnbaum, D. Assignment of vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) genes to human chromosome 6p12-p21 and 14q24-q31 regions, respectively. Genomics 32: 168-169, 1996. [PubMed: 8786112] [Full Text: https://doi.org/10.1006/geno.1996.0098]
Maynard, S. E., Min, J.-Y., Merchan, J., Lim, K.-H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., Epstein, F. H., Sukhatme, V. P., Karumanchi, S. A. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111: 649-658, 2003. [PubMed: 12618519] [Full Text: https://doi.org/10.1172/JCI17189]
Millauer, B., Shawver, L. K., Plate, K. H., Risau, W., Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576-579, 1994. [PubMed: 8107827] [Full Text: https://doi.org/10.1038/367576a0]
Miralles, G. D., O'Fallon, J. R., Talley, N. J. Plasma-cell dyscrasia with polyneuropathy: the spectrum of POEMS syndrome. New Eng. J. Med. 327: 1919-1923, 1992. [PubMed: 1333569] [Full Text: https://doi.org/10.1056/NEJM199212313272705]
Mueller, M. D., Vigne, J.-L., Minchenko, A., Lebovic, D. I., Leitman, D. C., Taylor, R. N. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc. Nat. Acad. Sci. 97: 10972-10977, 2000. [PubMed: 10995484] [Full Text: https://doi.org/10.1073/pnas.200377097]
Nakanishi, T., Sobue, I., Toyokura, Y., Nishitani, H., Kuroiwa, Y., Satoyoshi, E., Tsubaki, T., Igata, A., Ozaki, Y. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 34: 712-720, 1984. [PubMed: 6539431] [Full Text: https://doi.org/10.1212/wnl.34.6.712]
Niimi, H., Arimura, K., Jonosono, M., Hashiguchi, T., Kawabata, M., Osame, M., Kitajima, I. VEGF is causative for pulmonary hypertension in a patient with Crow-Fukase (POEMS) syndrome. Intern. Med. 39: 1101-1104, 2000. [PubMed: 11197800] [Full Text: https://doi.org/10.2169/internalmedicine.39.1101]
Nobile-Orazio, E., Terenghi, F., Giannotta, C., Gallia, F., Nozza, A. Serum VEGF levels in POEMS syndrome and in immune-mediated neuropathies. Neurology 72: 1024-1026, 2009. [PubMed: 19289745] [Full Text: https://doi.org/10.1212/01.wnl.0000344569.13496.ff]
Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444: 1032-1037, 2006. [PubMed: 17183313] [Full Text: https://doi.org/10.1038/nature05355]
Nozaki, M., Sakurai, E., Raisler, B. J., Baffi, J. Z., Witta, J., Ogura, Y., Brekken, R. A., Sage, E. H., Ambati, B. K., Ambati, J. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J. Clin. Invest. 116: 422-429, 2006. [PubMed: 16453023] [Full Text: https://doi.org/10.1172/JCI26316]
Ogata, N., Nishikawa, M., Nishimura, T., Mitsuma, Y., Matsumura, M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am. J. Ophthal. 134: 348-353, 2002. [PubMed: 12208245] [Full Text: https://doi.org/10.1016/s0002-9394(02)01568-4]
Onesto, C., Berra, E., Grepin, R., Pages, G. Poly(A)-binding protein-interacting protein 2, a strong regulator of vascular endothelial growth factor mRNA. J. Biol. Chem. 279: 34217-34226, 2004. [PubMed: 15175342] [Full Text: https://doi.org/10.1074/jbc.M400219200]
Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., Van Dorpe, J., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., and 20 others. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genet. 28: 131-138, 2001. [PubMed: 11381259] [Full Text: https://doi.org/10.1038/88842]
Poltorak, Z., Cohen, T., Sivan, R., Kandelis, Y., Spira, G., Vlodavsky, I., Keshet, E., Neufeld, G. VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J. Biol. Chem. 272: 7151-7158, 1997. [PubMed: 9054410] [Full Text: https://doi.org/10.1074/jbc.272.11.7151]
Poulaki, V., Mitsiades, C. S., McMullan, C., Sykoutri, D., Fanourakis, G., Kotoula, V., Tseleni-Balafouta, S., Koutras, D. A., Mitsiades, N. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas. J. Clin. Endocr. Metab. 88: 5392-5398, 2003. [PubMed: 14602779] [Full Text: https://doi.org/10.1210/jc.2003-030389]
Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., Anand-Apte, B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med. 9: 407-415, 2003. [PubMed: 12652295] [Full Text: https://doi.org/10.1038/nm846]
Rao, S., Chun, C., Fan, J., Kofron, J. M., Yang, M. B., Hegde, R. S., Ferrara, N., Copenhagen, D. R., Lang, R. A. A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature 494: 243-246, 2013. [PubMed: 23334418] [Full Text: https://doi.org/10.1038/nature11823]
Ray, P. S., Jia, J., Yao, P., Majumder, M., Hatzoglou, M., Fox, P. L. A stress-responsive RNA switch regulates VEGFA expression. Nature 457: 915-919, 2009. [PubMed: 19098893] [Full Text: https://doi.org/10.1038/nature07598]
Ruhrberg, C., Gerhardt, H., Golding, M., Watson, R., Ioannidou, S., Fujisawa, H., Betscholtz, C., Shima, D. T. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16: 2684-2698, 2002. [PubMed: 12381667] [Full Text: https://doi.org/10.1101/gad.242002]
Shimpo, S. Solitary myeloma causing polyneuritis and endocrine disorders. Nippon Rinsho 26: 2444-2456, 1968. [PubMed: 5752014]
Simo, R., Lecube, A., Segura, R. M., Garcia Arumi, J., Hernandez, C. Free insulin growth factor-1 and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Am. J. Ophthal. 134: 376-382, 2002. [PubMed: 12208249] [Full Text: https://doi.org/10.1016/s0002-9394(02)01538-6]
Smith, C. L., Birdsey, G. M., Anthony, S., Arrigoni, F. I., Leiper, J. M., Vallance, P. Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochem. Biophys. Res. Commun. 308: 984-989, 2003. [PubMed: 12927816] [Full Text: https://doi.org/10.1016/s0006-291x(03)01507-9]
Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92: 735-745, 1998. [PubMed: 9529250] [Full Text: https://doi.org/10.1016/s0092-8674(00)81402-6]
Sone, H., Kawakami, Y., Sakauchi, M., Nakamura, Y., Takahashi, A., Shimano, H., Okuda, Y., Segawa, T., Suzuki, H., Yamada, N. Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis and ameliorates established disease in mice. Biochem. Biophys. Res. Commun. 281: 562-568, 2001. [PubMed: 11181084] [Full Text: https://doi.org/10.1006/bbrc.2001.4395]
Springer, M. L., Chen, A. S., Kraft, P. E., Bednarski, M., Blau, H. M. VEGF gene delivery to muscle: potential role for vasculogenesis in adults. Molec. Cell 2: 549-558, 1998. [PubMed: 9844628] [Full Text: https://doi.org/10.1016/s1097-2765(00)80154-9]
Stalmans, I., Lambrechts, D., De Smet, F., Jansen, S., Wang, J., Maity, S., Kneer, P., von der Ohe, M., Swillen, A., Maes, C., Gewillig, M., Molin, D. G. M., and 20 others. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nature Med. 9: 173-182, 2003. [PubMed: 12539040] [Full Text: https://doi.org/10.1038/nm819]
Stockmann, C., Doedens, A., Weidemann, A., Zhang, N., Takeda, N., Greenberg, J. I., Cheresh, D. A., Johnson, R. S. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456: 814-818, 2008. [PubMed: 18997773] [Full Text: https://doi.org/10.1038/nature07445]
Tam, B. Y. Y., Wei, K., Rudge, J. S., Hoffman, J., Holash, J., Park, S., Yuan, J., Hefner, C., Chartier, C., Lee, J.-S., Jiang, S., Nayak, N. R., and 11 others. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nature Med. 12: 793-800, 2006. Note: Erratum: Nature Med. 15: 462 only, 2009. [PubMed: 16799557] [Full Text: https://doi.org/10.1038/nm1428]
Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. N., Yancopoulos, G. D., McDonald, D. M. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286: 2511-2514, 1999. [PubMed: 10617467] [Full Text: https://doi.org/10.1126/science.286.5449.2511]
Tischer, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J. C., Abraham, J. A. The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266: 11947-11954, 1991. [PubMed: 1711045]
Van Vught, P. W. J., Sutedja, N. A., Veldink, J. H., Koeleman, B. P. C., Groeneveld, G. J., Wijmenga, C., Uitdehaag, B. M. J., de Jong, J. M. B. V., Baas, F., Wokke, J. H. J., Van den Berg, L. H. Lack of association between VEGF polymorphisms and ALS in a Dutch population. Neurology 65: 1643-1645, 2005. [PubMed: 16301496] [Full Text: https://doi.org/10.1212/01.wnl.0000184514.39853.56]
Vincenti, V., Cassano, C., Rocchi, M., Persico, M. G. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93: 1493-1495, 1996. [PubMed: 8608615] [Full Text: https://doi.org/10.1161/01.cir.93.8.1493]
Watanabe, D., Suzuma, K., Suzuma, I., Ohashi, H., Ojima, T., Kurimoto, M., Murakami, T., Kimura, T., Takagi, H. Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am. J. Ophthal. 139: 476-481, 2005. [PubMed: 15767056] [Full Text: https://doi.org/10.1016/j.ajo.2004.10.004]
Watanabe, O., Maruyama, I., Arimura, K., Kitajima, I., Arimura, H., Hanatani, M., Matsuo, K., Arisato, T., Osame, M. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome. Muscle Nerve 21: 1390-1397, 1998. [PubMed: 9771661] [Full Text: https://doi.org/10.1002/(sici)1097-4598(199811)21:11<1390::aid-mus5>3.0.co;2-4]
Wei, M.-H., Popescu, N. C., Lerman, M. I., Merrill, M. J., Zimonjic, D. B. Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6p12. Hum. Genet. 97: 794-797, 1996. [PubMed: 8641698]
Wong, A. K., Alfert, M., Castrillon, D. H., Shen, Q., Holash, J., Yancopoulos, G. D., Chin, L. Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome. Proc. Nat. Acad. Sci. 98: 7481-7486, 2001. [PubMed: 11404464] [Full Text: https://doi.org/10.1073/pnas.121192298]
Wulff, C., Wilson, H., Largue, P., Duncan, W. C., Armstrong, D. G., Fraser, H. M. Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, Tie-2, and vascular endothelial growth factor messenger ribonucleic acid. J. Clin. Endocr. Metab. 85: 4302-4309, 2000. [PubMed: 11095472] [Full Text: https://doi.org/10.1210/jcem.85.11.6942]
Yao, Y.-G., Duh, E. J. VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis. Biochem. Biophys. Res. Commun. 321: 648-656, 2004. [PubMed: 15358155] [Full Text: https://doi.org/10.1016/j.bbrc.2004.06.176]
Ylikorkala, A., Rossi, D. J., Korsisaari, N., Luukko, K., Alitalo, K., Henkemeyer, M., Makela, T. P. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293: 1323-1326, 2001. [PubMed: 11509733] [Full Text: https://doi.org/10.1126/science.1062074]
Zarbock, R., Hendig, D., Szliska, C., Kleesiek, K., Gotting, C. Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum. Hum. Molec. Genet. 18: 3344-3351, 2009. [PubMed: 19483196] [Full Text: https://doi.org/10.1093/hmg/ddp259]

Contributors:

Bao Lige - updated : 05/30/2019
Ada Hamosh - updated : 10/10/2014
Patricia A. Hartz - updated : 8/26/2014
Ada Hamosh - updated : 2/26/2013
Ada Hamosh - updated : 4/24/2012
Ada Hamosh - updated : 11/29/2011
Cassandra L. Kniffin - updated : 3/17/2011
George E. Tiller - updated : 7/7/2010
Cassandra L. Kniffin - updated : 6/14/2010
Paul J. Converse - updated : 5/25/2010
Cassandra L. Kniffin - updated : 6/29/2009
Ada Hamosh - updated : 6/18/2009
Cassandra L. Kniffin - updated : 5/29/2009
Matthew B. Gross - updated : 5/14/2009
Ada Hamosh - updated : 3/9/2009
Marla J. F. O'Neill - updated : 2/12/2009
Ada Hamosh - updated : 1/29/2009
Ada Hamosh - updated : 4/15/2008
Ada Hamosh - updated : 3/18/2008
Jane Kelly - updated : 12/12/2007
Cassandra L. Kniffin -updated : 10/2/2007
Cassandra L. Kniffin - updated : 9/14/2007
Ada Hamosh - updated : 4/20/2007
Cassandra L. Kniffin - updated : 2/15/2007
Patricia A. Hartz - updated : 12/18/2006
Patricia A. Hartz - updated : 8/10/2006
Marla J. F. O'Neill - updated : 7/10/2006
Paul J. Converse - updated : 9/2/2005
Cassandra L. Kniffin - updated : 7/27/2005
Marla J. F. O'Neill - updated : 7/21/2005
Victor A. McKusick - updated : 7/5/2005
Jane Kelly - updated : 7/1/2005
John A. Phillips, III - updated : 4/20/2005
Marla J. F. O'Neill - updated : 2/18/2005
Patricia A. Hartz - updated : 2/4/2005
Victor A. McKusick - updated : 8/20/2004
Jane Kelly - updated : 7/28/2004
Ada Hamosh - updated : 6/11/2004
Marla J. F. O'Neill - updated : 3/12/2004
Jane Kelly - updated : 8/22/2003
Ada Hamosh - updated : 7/24/2003
Victor A. McKusick - updated : 7/7/2003
Ada Hamosh - updated : 6/17/2003
Cassandra L. Kniffin - updated : 5/15/2003
Patricia A. Hartz - updated : 4/21/2003
Ada Hamosh - updated : 4/15/2003
Jane Kelly - updated : 4/9/2003
Jane Kelly - updated : 4/7/2003
Ada Hamosh - updated : 4/1/2003
Jane Kelly - updated : 3/27/2003
Ada Hamosh - updated : 2/27/2003
Ada Hamosh - updated : 2/21/2003
John A. Phillips, III - updated : 12/16/2002
Jane Kelly - updated : 11/5/2002
Victor A. McKusick - updated : 10/11/2002
John A. Phillips, III - updated : 7/30/2002
Ada Hamosh - updated : 7/9/2002
Jane Kelly - updated : 7/2/2002
Jane Kelly - updated : 4/3/2002
Ada Hamosh - updated : 8/27/2001
John A. Phillips, III - updated : 8/17/2001
Victor A. McKusick - updated : 7/18/2001
John A. Phillips, III - updated : 7/6/2001
Victor A. McKusick - updated : 6/19/2001
Victor A. McKusick - updated : 6/1/2001
Ada Hamosh - updated : 5/2/2001
Ada Hamosh - updated : 4/20/2001
Victor A. McKusick - updated : 11/29/2000
Victor A. McKusick - updated : 10/26/2000
Paul J. Converse - updated : 6/8/2000
Ada Hamosh - updated : 5/10/2000
Ada Hamosh - updated : 12/27/1999
Ada Hamosh - updated : 6/23/1999
Ada Hamosh - updated : 6/17/1999
Stylianos E. Antonarakis - updated : 2/9/1999
Stylianos E. Antonarakis - updated : 9/30/1998
Stylianos E. Antonarakis - updated : 5/22/1998
Moyra Smith - Updated : 5/10/1996

Creation Date:

Victor A. McKusick : 9/11/1991

Edit History:

mgross : 05/30/2019
carol : 05/15/2018
carol : 11/13/2017
carol : 08/04/2016
alopez : 08/31/2015
alopez : 10/10/2014
mgross : 8/26/2014
carol : 8/21/2014
mcolton : 8/21/2014
carol : 2/17/2014
carol : 2/3/2014
alopez : 3/4/2013
terry : 2/26/2013
terry : 5/10/2012
alopez : 4/25/2012
terry : 4/24/2012
alopez : 12/1/2011
terry : 11/29/2011
wwang : 6/13/2011
terry : 4/26/2011
wwang : 3/28/2011
ckniffin : 3/17/2011
ckniffin : 3/17/2011
wwang : 7/20/2010
wwang : 7/7/2010
terry : 7/7/2010
wwang : 6/18/2010
ckniffin : 6/14/2010
wwang : 5/25/2010
wwang : 3/1/2010
wwang : 7/29/2009
ckniffin : 6/29/2009
alopez : 6/24/2009
terry : 6/18/2009
wwang : 6/3/2009
ckniffin : 5/29/2009
wwang : 5/29/2009
mgross : 5/14/2009
mgross : 4/29/2009
alopez : 3/11/2009
alopez : 3/10/2009
terry : 3/9/2009
carol : 2/19/2009
carol : 2/13/2009
carol : 2/12/2009
alopez : 2/6/2009
terry : 1/29/2009
carol : 9/24/2008
alopez : 5/16/2008
alopez : 5/16/2008
terry : 4/15/2008
alopez : 3/26/2008
terry : 3/18/2008
carol : 12/12/2007
wwang : 10/8/2007
ckniffin : 10/2/2007
wwang : 9/21/2007
ckniffin : 9/14/2007
alopez : 4/24/2007
terry : 4/20/2007
wwang : 2/19/2007
ckniffin : 2/15/2007
wwang : 12/20/2006
terry : 12/18/2006
wwang : 11/8/2006
mgross : 8/10/2006
terry : 8/10/2006
wwang : 7/11/2006
terry : 7/10/2006
mgross : 9/2/2005
carol : 8/12/2005
carol : 8/12/2005
wwang : 8/9/2005
ckniffin : 7/27/2005
ckniffin : 7/27/2005
wwang : 7/25/2005
terry : 7/21/2005
wwang : 7/6/2005
terry : 7/5/2005
alopez : 7/1/2005
alopez : 4/20/2005
terry : 3/11/2005
wwang : 2/23/2005
terry : 2/18/2005
mgross : 2/4/2005
terry : 11/4/2004
tkritzer : 8/23/2004
terry : 8/20/2004
tkritzer : 7/28/2004
alopez : 6/15/2004
alopez : 6/15/2004
terry : 6/11/2004
carol : 4/27/2004
tkritzer : 3/25/2004
tkritzer : 3/12/2004
alopez : 9/2/2003
mgross : 8/22/2003
alopez : 7/28/2003
carol : 7/24/2003
terry : 7/24/2003
alopez : 7/10/2003
terry : 7/7/2003
alopez : 6/18/2003
terry : 6/17/2003
cwells : 5/20/2003
ckniffin : 5/15/2003
cwells : 4/24/2003
terry : 4/21/2003
alopez : 4/17/2003
terry : 4/15/2003
cwells : 4/9/2003
cwells : 4/7/2003
alopez : 4/3/2003
terry : 4/1/2003
cwells : 3/27/2003
alopez : 3/4/2003
terry : 2/27/2003
alopez : 2/25/2003
terry : 2/21/2003
alopez : 12/16/2002
carol : 11/5/2002
tkritzer : 10/28/2002
tkritzer : 10/16/2002
terry : 10/11/2002
tkritzer : 7/31/2002
tkritzer : 7/30/2002
alopez : 7/10/2002
terry : 7/9/2002
mgross : 7/2/2002
terry : 6/26/2002
mgross : 4/3/2002
mgross : 4/3/2002
carol : 10/24/2001
cwells : 9/4/2001
cwells : 8/29/2001
terry : 8/27/2001
mgross : 8/17/2001
mcapotos : 8/9/2001
mcapotos : 8/9/2001
mcapotos : 7/27/2001
terry : 7/18/2001
alopez : 7/6/2001
mcapotos : 6/25/2001
mcapotos : 6/19/2001
terry : 6/19/2001
mcapotos : 6/4/2001
terry : 6/1/2001
alopez : 5/7/2001
terry : 5/2/2001
alopez : 4/30/2001
terry : 4/20/2001
mcapotos : 12/18/2000
terry : 11/29/2000
mcapotos : 11/8/2000
mcapotos : 11/1/2000
terry : 10/26/2000
carol : 6/8/2000
alopez : 5/10/2000
carol : 5/10/2000
alopez : 12/27/1999
alopez : 6/23/1999
alopez : 6/17/1999
mgross : 4/7/1999
mgross : 2/9/1999
carol : 9/30/1998
carol : 5/22/1998
jenny : 4/21/1997
mark : 10/21/1996
carol : 8/23/1996
carol : 5/15/1996
carol : 5/15/1996
carol : 5/10/1996
mark : 4/4/1996
terry : 4/4/1996
mark : 3/13/1996
mark : 3/11/1996
terry : 3/7/1996
mark : 11/14/1995
supermim : 3/16/1992
carol : 9/11/1991

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM^® and Online Mendelian Inheritance in Man^® are registered trademarks of the Johns Hopkins University.
Copyright^® 1966-2024 Johns Hopkins University.
Printed: May 4, 2024

▼ External Links

VASCULAR ENDOTHELIAL GROWTH FACTOR A; VEGFA

VEGF

TEXT

▼ Description

▼ Cloning and Expression

▼ Gene Structure

▼ Gene Function

▼ Biochemical Features

▼ Mapping

▼ Molecular Genetics

▼ Animal Model

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 1

.0002 RECLASSIFIED - VASCULAR ENDOTHELIAL GROWTH FACTOR A POLYMORPHISM

▼ REFERENCES

* 192240

VASCULAR ENDOTHELIAL GROWTH FACTOR A; VEGFA

VEGF

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Gene Structure

Gene Function

Biochemical Features

Mapping

Molecular Genetics

Animal Model

ALLELIC VARIANTS 2 Selected Examples):

.0001 MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 1

.0002 RECLASSIFIED - VASCULAR ENDOTHELIAL GROWTH FACTOR A POLYMORPHISM

REFERENCES

▼

External Links