* 165070

FMS-RELATED TYROSINE KINASE 1; FLT1


Alternative titles; symbols

ONCOGENE FLT; FLT
VASCULAR ENDOTHELIAL GROWTH FACTOR/VASCULAR PERMEABILITY FACTOR RECEPTOR
VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 1; VEGFR1


HGNC Approved Gene Symbol: FLT1

Cytogenetic location: 13q12.3     Genomic coordinates (GRCh38): 13:28,300,346-28,495,128 (from NCBI)


TEXT

Description

Oncogene FLT belongs to the src gene family and is related to oncogene ROS (165020). Like other members of this family, it shows tyrosine protein kinase activity that is important for the control of cell proliferation and differentiation. The sequence structure of the FLT gene resembles that of the FMS gene (164770); hence, Yoshida et al. (1987) proposed the name FLT as an acronym for FMS-like tyrosine kinase.


Cloning and Expression

Shibuya et al. (1990) cloned full-length FLT1 from normal human placenta RNA. The deduced 1,338-amino acid protein has a calculated molecular mass of 150.6 kD. It has a 758-amino acid extracellular domain, followed by a 22-amino acid transmembrane region and a 558-amino acid cytoplasmic region containing a cluster of basic amino acids and a tyrosine kinase domain. The kinase domain has 3 conserved glycines (G834, G836, and G839), a conserved lysine (K861) involved in ATP binding, and a putative tyrosine autophosphorylation site (Y1053). Northern blot analysis detected a transcript of about 8.0 kb that was highly expressed in placenta and more weakly expressed in liver, muscle, and kidney. Weak expression was also detected in kidney cell lines and a choriocarcinoma cell line. Rat Flt1 was widely expressed in normal tissues, with highest expression in lung.

Kendall and Thomas (1993) stated that the extracellular ligand-binding region of full-length FLT1 has an N-terminal signal peptide followed by 7 immunoglobulin-like domains. Using a probe encoding the extracellular domain of FLT1 to screen a human umbilical vein endothelial cell (HUVEC) cDNA library, Kendall and Thomas (1993) obtained 2 cDNAs with different 5-prime and 3-prime ends. Both cDNAs encode the same truncated soluble form of FLT1, which Kendall and Thomas (1993) designated sFLT. The deduced 687-amino acid protein contains the secretory leader sequence and 6 of the 7 N-terminal extracellular immunoglobulin domains of full-length FLT1, but it lacks the transmembrane and kinase domains and terminates in 31 unique C-terminal amino acids. It also has 12 N-glycosylation sites. Sequencing of mature sFLT revealed that the N terminus began with ser27, suggesting cleavage of the leader sequence.

By EST database analysis, followed by RACE of preeclamptic (see 189800) placenta, Sela et al. (2008) cloned an additional splice variant encoding a soluble form of FLT1 that they called sFLT1-14. This transcript has a unique 3-prime end due to use of a splice acceptor site within intron 14. The deduced 733-amino acid protein has only the extracellular domain of full-length FLT1, and it has a unique C terminus relative to the sFLT1 isoform. Northern blot analysis showed that endothelial cells from human saphenous vein and radial artery expressed full-length FLT1 and sFLT1, whereas vascular smooth muscle cells from the same vessels expressed only sFLT1-14. Western blot analysis of transfected HeLa cells detected a cell-associated sFLT1-14 protein at an apparent molecular mass of 115 kD and a secreted form at 130 kD.


Gene Function

Kendall and Thomas (1993) showed that recombinant sFLT bound vascular endothelial growth factor (VEGF; 192240) with high affinity. In culture, sFLT competed with FLT1 receptors on HUVECs for binding to radiolabeled VEGF. Furthermore, sFLT eliminated VEGF-induced mitogenesis of HUVECs in a concentration-dependent manner.

Kendall et al. (1996) showed that endogenous sFLT identified in the conditioned culture medium of HUVECs bound VEGF with high affinity comparable to that of recombinant sFLT. They found that sFLT1 and FLK1 (KDR; 191306) formed heterodimers in vitro. Because sFLT1 had a higher affinity for VEGF than for FLK1, Kendall et al. (1996) suggested that sFLT1 may function as an inhibitor of VEGF response.

Wiesmann et al. (1997) reported the results of domain deletion studies of the extracellular portion of FLT1. They showed that FLT1 domains 2 and 3 are necessary and sufficient for binding VEGF with near-native affinity and that domain 2 alone binds only 60-fold less tightly than wildtype.

He et al. (1999) described a mouse cDNA sequence encoding sFLT1 that is a potent antagonist to VEGF and showed its in vivo production. In situ hybridization and Northern blot analysis with probes specific for sFLT1 or FLT1 showed that the relative abundance of their mRNAs changed markedly in spongiotrophoblast cells in the placenta as gestation progressed. On day 11 of pregnancy, sFLT1 mRNA was undetectable but FLT1 was readily apparent, and by day 17 sFLT1 mRNA was abundant but FLT1 was barely detectable. The authors concluded that these data suggest a novel mechanism of regulation of angiogenesis by alternative splicing of FLT1 pre-mRNA.

Wulff et al. (2001) examined the effects of a soluble truncated form of FLT1, vascular endothelial growth factor trapA40 (VEGF trap), in a primate model to determine its ability to prevent the onset of luteal angiogenesis or intervene with the ongoing process. Marmosets were treated from the day of ovulation until luteal day 3 (prevention regimen) or on luteal day 3 for 1 day (intervention regimen). After both treatments, intense luteal endothelial proliferation was suppressed, a concomitant decrease in endothelial cell area confirmed the inhibition of vascular development, and a marked fall in plasma progesterone levels showed that luteal function was compromised. The authors concluded that the VEGF trap can prevent luteal angiogenesis and inhibit the established process with resultant suppression of luteal function; that luteal FLT mRNA expression is dependent upon VEGF; and that VEGF inhibition results in abortive increases in expression of VEGF, angiopoietin-2 (601922), and TIE2 (600221).

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 (192240) 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.

Autiero et al. (2003) reported that placental growth factor (PGF; 601121) regulates inter- and intramolecular cross-talk between the VEGF receptor tyrosine kinases FLT1 and FLK1. 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 (see 189800) women, Maynard et al. (2003) found increased 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.

In 120 preeclamptic women and 120 matched, normotensive controls, Levine et al. (2004) measured serum levels of the angiogenic factors sFLT1, PGF, and VEGF throughout pregnancy. During the last 2 months of pregnancy in the normotensive controls, the level of sFLT1 increased and the level of PGF decreased; these changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. At the onset of clinical disease, the mean serum level of sFLT1 in the preeclamptic women was significantly higher than that of controls with fetuses of similar gestational age (p less than 0.001). PGF levels were significantly lower in women who later had preeclampsia than in controls, beginning at 13 to 16 weeks of gestation (p = 0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with an increase in the sFLT1 level. Levine et al. (2004) concluded that increased levels of sFLT1 and reduced levels of PGF predict the subsequent development of preeclampsia.

Kaplan et al. (2005) demonstrated that bone marrow-derived hematopoietic progenitor cells that express VEGFR1 home to tumor-specific premetastatic sites and form cellular clusters before the arrival of tumor cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1-positive cells from the bone marrow of wildtype mice abrogated the formation of these premetastatic clusters and prevented tumor metastasis, whereas reconstitution with selected Id3 (600277)-competent VEGFR1-positive cells established cluster formation and tumor metastasis in Id3 knockout mice. Kaplan et al. (2005) also showed that VEGFR1-positive cells express VLA4, also known as integrin alpha-4-beta-1 (see 192975), and that tumor-specific growth factors upregulate fibronectin (135600), a VLA4 ligand, in resident fibroblasts, providing a permissive niche for incoming tumor cells. Conditioned media obtained from distinct tumor types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. Kaplan et al. (2005) concluded that their findings demonstrated a requirement for VEGFR1-positive hematopoietic progenitors in the regulation of metastasis, and suggested that expression patterns of fibronectin and VEGFR1-positive-VLA4-positive clusters dictate organ-specific tumor spread.

Ambati et al. (2006) showed that the cornea expresses soluble VEGF receptor-1, also known as SFLT1, and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference, or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 (see 609114) and Pax6 heterozygous mice (see 607108) and Pax6 heterozygous patients with aniridia (106210) are deficient in SFLT1, and recombinant Sflt1 administration restores corneal avascularity in corn1 and Pax6 heterozygous mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt1, whereas the avascular corneas of dugongs (also members of the order Sirenia), elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt1, indicating that it has a crucial, evolutionarily conserved role.

Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor A (VEGFA; 192240) or its receptor VEGFR1 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.

Using porcine aortic endothelial cells expressing human VEGFR2 (KDR), Sela et al. (2008) showed that both sFLT1 and sFLT1-14 inhibited VEGFR2 phosphorylation in a dose-dependent manner. Northern blot analysis of normal placenta showed that expression of soluble FLT1 transcripts increased progressively, and the increase was predominantly due to increased expression of sFLT1-14, which became the dominant transcript at the beginning of the second trimester. Expression of sFLT1-14 was further elevated in preeclamptic placentas. In situ hybridization showed that sFLT1-14 was expressed in syncytial knots characteristic of preeclamptic placentas, as well as in the many fewer syncytial knots formed in older normal placentas. Expression of sFLT1-14 was much lower in normal syncytiotrophoblasts. ELISA analysis detected sFLT1-14 in sera of preeclamptic women.

Stefater et al. (2011) showed that during development, retinal myeloid cells produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in retinal myeloid cells of the Wnt ligand transporter Wntless (611514) results in increased angiogenesis in the deeper layers. Stefater et al. (2011) also showed that mutation of Wnt5a (164975) and Wnt11 (603699) results in increased angiogenesis and that these ligands elicit retinal myeloid cell responses via a noncanonical Wnt pathway. Using cultured myeloid-like cells and retinal myeloid cell somatic deletion of Flt1, Stefater et al. (2011) showed that Flt1, a naturally occurring inhibitor of VEGF, is an effector of Wnt-dependent suppression of angiogenesis by retinal myeloid cells. Stefater et al. (2011) concluded that resident myeloid cells can use a noncanonical, Wnt-Flt1 pathway to suppress angiogenic branching.

Zhang et al. (2018) showed that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of neuropilin-1 (NRP1; 602069) and Vegfr1 (Flt1) renders mice resistant to diet-induced obesity. Absence of Nrp1 and Flt1 receptors increased Vegfa (192240) bioavailability and signaling through Vegfr2 (191306), inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by Vegfr2 and vascular endothelial cadherin (VE-cadherin; 601120) signaling inhibition rescued chylomicron transport in mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal VE-cadherin anchors prevented chylomicron uptake in wildtype mice.


Gene Structure

Sela et al. (2008) reported that the FLT1 gene contains at least 30 coding exons, all of which are included in the full-length FLT1 transcript. Use of alternative splice acceptor sites within introns 13 and 14 produces transcripts encoding the truncated soluble isoforms sFLT1 and sFLT1-14, respectively.


Mapping

Satoh et al. (1987) and Yoshida et al. (1987) mapped FLT to 13q12 by probing of DNA from a panel of human-mouse somatic cell hybrids and by in situ hybridization. By the isolation and analysis of a YAC containing the FLT1 and FLT3 (136351) genes, Imbert et al. (1994) confirmed their close physical linkage. FLT1 and FLT3 are linked in a head-to-tail configuration and are separated by about 150 kb. Imbert et al. (1994) found that the region contains 3 CpG islands, 2 of which were thought to correspond to FLT1 and FLT3 and the third to a putative, unidentified receptor-type tyrosine kinase (RTK) gene. They referred to studies performed by fluorescence in situ hybridization using the YAC as a probe.


Biochemical Features

Crystal Structure

Wiesmann et al. (1997) reported the crystal structure to 1.7-angstrom resolution of the complex between the receptor-binding domain of VEGF and FLT1 domain 2. The crystal structure of the complex between VEGF and the second domain of FLT1 shows domain 2 in a predominantly hydrophobic interaction with the 'poles' of the VEGF dimer. Based on this structure and on mutational data, Wiesmann et al. (1997) presented a model of VEGF bound to the first 4 domains of FLT1.

Role in Peripartum Cardiomyopathy Susceptibility

To test the idea that angiogenic signaling can cause cardiac dysfunction in pregnant women, Patten et al. (2012) studied women with preeclampsia (see 189800) who had compromised VEGF (192240) signaling due to high serum levels of antiangiogenic sFLT1. Cardiac function was evaluated noninvasively by measuring the myocardial performance index (MPI) and other indices of cardiac function with cardiac echocardiography. Women with preeclampsia had markedly increased serum levels of sFLT1 (p = 0.005), as previously shown by Levine et al. (2004). Notably, women with preeclampsia also had a markedly abnormal MPI and other indicators of cardiac diastolic dysfunction. The MPI correlated with levels of circulating sFLT1 (R = 0.59, p = 0.003). To test this idea directly, Patten et al. (2012) delivered sFLT1 systemically to pregnant mice by intravenous injection of adenoviruses expressing sFLT1 and examined MPI using high-resolution murine echocardiography. sFLT1 caused significant increases in MPI in these mice within 10 days. Patten et al. (2012) concluded that their data, taken together with published observations in patients receiving antiangiogenic therapies, strongly suggested that elevated sFLT1 causes cardiac dysfunction in women with preeclampsia.

Patten et al. (2012) collected plasma from women with peripartum cardiomyopathy (PPCM; 614670) 4 to 6 weeks postpartum and measured sFLT1 levels. sFLT1 levels usually return to normal within 48 to 72 hours after delivery. sFLT1 levels were elevated in a large subset of these PPCM patients (p = 0.002), remaining up to 5- to 10-fold higher than the levels of control participants. Postpartum sFLT1 levels can remain slightly higher in subjects with preeclampsia, but the levels found by Patten et al. (2012) in this subset of PPCM patients were notably higher. Thus, the findings were consistent with the idea that a substantial percentage of PPCM subjects have been exposed to preeclampsia, and that secretion of sFLT1 persists inappropriately postpartum. Among Harvard teaching hospitals included in the study by Patten et al. (2012), 33% of the last 75 cases of PPCM were associated with preeclampsia, markedly more than the population rate of 3 to 5%. The persisting extraplacental source of sFLT1 in the postpartum period was not known, and Patten et al. (2012) suggested that this source may include placental remnants, circulating mononuclear cells, or shed syncytial microparticles.

Patten et al. (2012) suggested that PPCM is caused by a 2-hit combination of, firstly, systemic antiangiogenic signals during late pregnancy, and, secondly, a host susceptibility marked by insufficient local proangiogenic defenses in the heart. The first hit explains why PPCM is a disease of the late gestational period, which is precisely when circulating antiangiogenic factors such as sFLT1 peak in pregnancy. The first hit is also worse in preeclampsia, which is characterized by markedly elevated sFLT1 levels. Patten et al. (2012) hypothesized a number of possible second hits, including abnormal PGC1-alpha (604517), myocarditis, immune activation, viral infection, and/or autoantibodies. Patten et al. (2012) concluded that their data supported the idea that PPCM is partly a 2-hit vascular disease due to imbalances in angiogenic signaling, and that antiangiogenic states such as preeclampsia or multiple gestation substantially worsen the severity of the disease. Their observations also suggested that proangiogenic therapies such as exogenous VEGF121, or removal of sFLT1 itself, may therefore be beneficial in PPCM.


Molecular Genetics

Fetal Loss in Placental Malaria

Placental malaria (PM; see 611162) is caused by P. falciparum-infected erythrocytes adhering to chondroitin sulfate A and sequestering in the maternal circulation of the placenta. The highest rates of PM and fetal loss are in first-time mothers. Muehlenbachs et al. (2008) showed that a dinucleotide repeat polymorphism approximately 3 kb downstream of the last exon of FLT1, rs3138582, was expressed within the FLT1 UTR. They classified dinucleotide repeat polymorphisms with more than 27 repeats as the long (L) allele and those with 27 repeats or less as the short (S) allele and investigated the relationship of FLT1 repeat length to poor outcomes caused by PM in Tanzanian mother-infant pairs. The newborn genotype distribution differed by birth order, with newborns of first-time mothers having a genotype distribution that was out of Hardy-Weinberg equilibrium during peak PM season, when significantly fewer SS homozygotes were born to these mothers. First-time mothers who were SS homozygous were more likely to report prior fetal loss than those with other genotypes. First-time mothers of SS homozygous offspring had higher plasma FLT1 levels during PM compared with first-time mothers of SL or LL offspring. Peripheral blood mononuclear cells stimulated with lipopolysaccharide showed increased expression of FLT1 mRNA and protein in infants with SS and SL genotypes than in those with LL genotype. Muehlenbachs et al. (2008) suggested that fetal genes such as FLT1 may modify maternal inflammation and may be under natural selection secondary to malaria.

Thyroid Cancer

Liu et al. (2008) explored a wide-range genetic basis for the involvement of genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC; see 188470). They found frequent copy gains of RTK genes including EGFR (131550), and VEGFR1, and in PIK3CA (171834) and PIK3CB (602925) in the P13K/Akt pathway. Copy number gain of VEGFR1 was found in 20 of 44 ATCs (46%) and 26 of 59 FTCs (44%). RTK gene copy gains were preferentially associated with phosphorylation of Akt, suggesting their dominant role in activating the P13K/Akt pathway. Liu et al. (2008) concluded that genetic alterations in the RTKs and P13K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.

Associations Pending Confirmation

For discussion of a possible association between variation near the FLT1 gene and risk of preeclampsia, see PEE1 (189800).


Animal Model

VEGF and its high-affinity binding receptors, the tyrosine kinases FLK1 and FLT1, are thought to be important for the development of embryonic vasculature. Studying transgenic mice in whom the Flk1 gene was disrupted, Shalaby et al. (1995) demonstrated a total failure of embryonic mice to develop blood vessels and failure of blood island formation in the yolk sac. Fong et al. (1995) reported that in mice Flt1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Transgenic mouse embryos homozygous for a targeted mutation in the Flt1 locus formed endothelial cells in both embryonic and extraembryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the blood islands of homozygous mice were abnormal, with angioblasts in the interior as well as on the periphery. Fong et al. (1995) suggested that the Flt1 signaling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.

Niida et al. (2005) stated that Csf1 (120420)-null mice are osteopetrotic and that those null for the Flt1 gene show mild osteoclast reduction without bone marrow suppression. They created double-knockout mice that exhibited severe osteoclast deficiency and did not have sufficient osteoclasts to form the bone marrow cavity. The cavity of double-knockout mice was gradually replaced with fibrous tissue, resulting in severe marrow hypoplasia and extramedullary hematopoiesis. The number of osteoblasts was also decreased. Niida et al. (2005) concluded that FLT1 and CSF1 receptors play predominant roles in osteoclastogenesis and the maintenance of bone marrow function.

Using a transgenic mouse model of rheumatoid arthritis (RA; 180300) and antibodies to Vegf, Vegfr1, and Vegfr2, De Bandt et al. (2003) found that synovial cells from arthritic joints expressed all 3 proteins. Treatment with anti-Vegfr1 strongly attenuated the disease throughout the study period, whereas anti-Vegf transiently delayed disease onset and anti-Vegfr2 treatment had no effect. Histologic analysis showed that treatment with a VEGFR1 tyrosine kinase inhibitor nearly abolished the disease. De Bandt et al. (2003) concluded that VEGF is a key factor in pannus development, acting through the VEGFR1 pathway, and they proposed that VEGFR1 inhibitors may be useful in the treatment of RA.

In laser-injury studies in mice, Nozaki et al. (2006) observed that injury-induced choroidal neovascularization (CNV) was increased by excess Vegf before injury but was suppressed by Vegf after injury. This effect was mediated via Vegfr1 activation and Vegfr2 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.

Since Flt1 is a decoy receptor for vascular endothelial growth factor (VEGF; 192240), both homozygous (Flt1 -/-) and heterozygous (Flt1 +/-) Flt1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. In addition to its presence in muscle, dystrophin (300377) is also found in vasculature, and its absence results in vascular deficiency and abnormal blood flow. To create a mouse model of Duchenne muscular dystrophy (DMD; 310200) with increased vasculature, Verma et al. (2010) crossed mdx mice with Flt1 knockout mice. Flt1 +/- and mdx:Flt1 +/- adult mice displayed a developmentally increased vascular density in skeletal muscle compared with wildtype and mdx mice, respectively. The mdx:Flt1 +/- mice showed improved muscle histology compared with mdx mice, with decreased fibrosis, calcification, and membrane permeability. Functionally, the mdx:Flt1 +/- mice had an increase in muscle blood flow and force production compared with mdx mice. Because utrophin (128240) is upregulated in mdx mice and can compensate for the lacking function of dystrophin, Verma et al. (2010) created a triple-mutant mouse (mdx:utrophin -/-:Flt1 +/-). The mdx:utrophin -/-:Flt1 +/- mice also displayed improved muscle histology and significantly higher survival rates compared with mdx:utrophin -/- mice, which showed more severe muscle phenotypes than mdx mice. Verma et al. (2010) suggested that increasing the vasculature in DMD may ameliorate the histologic and functional phenotypes associated with this disease.


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  16. Niida, S., Kondo, T., Hiratsuka, S., Hayashi, S.-I., Amizuka, N., Noda, T., Ikeda, K., Shibuya, M. VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc. Nat. Acad. Sci. 102: 14016-14021, 2005. [PubMed: 16172397, images, related citations] [Full Text]

  17. 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]

  18. Patten, I. S., Rana, S., Shahul, S., Rowe, G. C., Jang, C., Liu, L., Hacker, M. R., Rhee, J. S., Mitchell, J., Mahmood, F., Hess, P., Farrell, C., and 9 others. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485: 333-338, 2012. [PubMed: 22596155, images, related citations] [Full Text]

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  22. Shibuya, M., Yamaguchi, S., Yamane, A., Ikeda, T., Tojo, A., Matsushime, H., Sato, M. Nucleotide sequence and expression of a novel human receptor-type tyrosine-kinase gene (flt) closely related to the fms family. Oncogene 5: 519-524, 1990. [PubMed: 2158038, related citations]

  23. Stefater, J. A., III, Lewkowich, I., Rao, S., Mariggi, G., Carpenter, A. C., Burr, A. R., Fan, J., Ajima, R., Molkentin, J. D., Williams, B. O., Wills-Karp, M., Pollard, J. W., Yamaguchi, T., Ferrara, N., Gerhardt, H., Lang, R. A. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474: 511-515, 2011. [PubMed: 21623369, images, related citations] [Full Text]

  24. Verma, M., Asakura, Y., Hirai, H., Watanabe, S., Tastad, C., Fong, G.-H., Ema, M., Call, J. A., Lowe, D. A., Asakura, A. Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice. Hum. Molec. Genet. 19: 4145-4159, 2010. [PubMed: 20705734, images, related citations] [Full Text]

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Ada Hamosh - updated : 09/24/2018
George E. Tiller - updated : 06/22/2017
Ada Hamosh - updated : 5/30/2012
Ada Hamosh - updated : 7/1/2011
Patricia A. Hartz - updated : 7/15/2009
John A. Phillips, III - updated : 5/7/2009
Paul J. Converse - updated : 4/23/2009
Ada Hamosh - updated : 4/15/2008
Ada Hamosh - updated : 12/6/2006
Marla J. F. O'Neill - updated : 7/10/2006
Ada Hamosh - updated : 5/26/2006
Paul J. Converse - updated : 4/11/2006
Patricia A. Hartz - updated : 3/10/2006
Marla J. F. O'Neill - updated : 2/18/2005
Ada Hamosh - updated : 6/17/2003
Ada Hamosh - updated : 2/21/2003
John A. Phillips, III - updated : 3/12/2002
John A. Phillips, III - updated : 6/28/2001
Stylianos E. Antonarakis - updated : 12/19/1997
Jennifer P. Macke - updated : 6/6/1997
Creation Date:
Victor A. McKusick : 9/2/1987
alopez : 09/24/2018
alopez : 09/06/2017
carol : 06/27/2017
alopez : 06/22/2017
alopez : 12/03/2013
alopez : 6/4/2012
terry : 5/30/2012
alopez : 7/6/2011
terry : 7/1/2011
carol : 5/20/2010
mgross : 7/20/2009
mgross : 7/17/2009
mgross : 7/17/2009
terry : 7/15/2009
alopez : 5/7/2009
alopez : 5/7/2009
alopez : 5/7/2009
mgross : 5/4/2009
mgross : 5/4/2009
terry : 4/23/2009
alopez : 5/16/2008
alopez : 5/15/2008
terry : 4/15/2008
alopez : 12/13/2006
terry : 12/6/2006
wwang : 7/11/2006
terry : 7/10/2006
alopez : 6/7/2006
terry : 5/26/2006
mgross : 5/1/2006
terry : 4/11/2006
wwang : 3/27/2006
terry : 3/10/2006
wwang : 3/1/2005
terry : 2/18/2005
alopez : 7/28/2003
alopez : 6/18/2003
terry : 6/17/2003
terry : 6/17/2003
alopez : 2/25/2003
terry : 2/21/2003
alopez : 3/12/2002
alopez : 10/30/2001
cwells : 7/3/2001
cwells : 6/28/2001
alopez : 5/7/2001
terry : 11/13/1998
carol : 7/29/1998
carol : 12/19/1997
alopez : 9/10/1997
alopez : 9/10/1997
jamie : 10/30/1996
mark : 7/5/1995
terry : 10/31/1994
supermim : 3/16/1992
carol : 1/3/1991
supermim : 3/20/1990
carol : 3/9/1990

* 165070

FMS-RELATED TYROSINE KINASE 1; FLT1


Alternative titles; symbols

ONCOGENE FLT; FLT
VASCULAR ENDOTHELIAL GROWTH FACTOR/VASCULAR PERMEABILITY FACTOR RECEPTOR
VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 1; VEGFR1


HGNC Approved Gene Symbol: FLT1

Cytogenetic location: 13q12.3     Genomic coordinates (GRCh38): 13:28,300,346-28,495,128 (from NCBI)


TEXT

Description

Oncogene FLT belongs to the src gene family and is related to oncogene ROS (165020). Like other members of this family, it shows tyrosine protein kinase activity that is important for the control of cell proliferation and differentiation. The sequence structure of the FLT gene resembles that of the FMS gene (164770); hence, Yoshida et al. (1987) proposed the name FLT as an acronym for FMS-like tyrosine kinase.


Cloning and Expression

Shibuya et al. (1990) cloned full-length FLT1 from normal human placenta RNA. The deduced 1,338-amino acid protein has a calculated molecular mass of 150.6 kD. It has a 758-amino acid extracellular domain, followed by a 22-amino acid transmembrane region and a 558-amino acid cytoplasmic region containing a cluster of basic amino acids and a tyrosine kinase domain. The kinase domain has 3 conserved glycines (G834, G836, and G839), a conserved lysine (K861) involved in ATP binding, and a putative tyrosine autophosphorylation site (Y1053). Northern blot analysis detected a transcript of about 8.0 kb that was highly expressed in placenta and more weakly expressed in liver, muscle, and kidney. Weak expression was also detected in kidney cell lines and a choriocarcinoma cell line. Rat Flt1 was widely expressed in normal tissues, with highest expression in lung.

Kendall and Thomas (1993) stated that the extracellular ligand-binding region of full-length FLT1 has an N-terminal signal peptide followed by 7 immunoglobulin-like domains. Using a probe encoding the extracellular domain of FLT1 to screen a human umbilical vein endothelial cell (HUVEC) cDNA library, Kendall and Thomas (1993) obtained 2 cDNAs with different 5-prime and 3-prime ends. Both cDNAs encode the same truncated soluble form of FLT1, which Kendall and Thomas (1993) designated sFLT. The deduced 687-amino acid protein contains the secretory leader sequence and 6 of the 7 N-terminal extracellular immunoglobulin domains of full-length FLT1, but it lacks the transmembrane and kinase domains and terminates in 31 unique C-terminal amino acids. It also has 12 N-glycosylation sites. Sequencing of mature sFLT revealed that the N terminus began with ser27, suggesting cleavage of the leader sequence.

By EST database analysis, followed by RACE of preeclamptic (see 189800) placenta, Sela et al. (2008) cloned an additional splice variant encoding a soluble form of FLT1 that they called sFLT1-14. This transcript has a unique 3-prime end due to use of a splice acceptor site within intron 14. The deduced 733-amino acid protein has only the extracellular domain of full-length FLT1, and it has a unique C terminus relative to the sFLT1 isoform. Northern blot analysis showed that endothelial cells from human saphenous vein and radial artery expressed full-length FLT1 and sFLT1, whereas vascular smooth muscle cells from the same vessels expressed only sFLT1-14. Western blot analysis of transfected HeLa cells detected a cell-associated sFLT1-14 protein at an apparent molecular mass of 115 kD and a secreted form at 130 kD.


Gene Function

Kendall and Thomas (1993) showed that recombinant sFLT bound vascular endothelial growth factor (VEGF; 192240) with high affinity. In culture, sFLT competed with FLT1 receptors on HUVECs for binding to radiolabeled VEGF. Furthermore, sFLT eliminated VEGF-induced mitogenesis of HUVECs in a concentration-dependent manner.

Kendall et al. (1996) showed that endogenous sFLT identified in the conditioned culture medium of HUVECs bound VEGF with high affinity comparable to that of recombinant sFLT. They found that sFLT1 and FLK1 (KDR; 191306) formed heterodimers in vitro. Because sFLT1 had a higher affinity for VEGF than for FLK1, Kendall et al. (1996) suggested that sFLT1 may function as an inhibitor of VEGF response.

Wiesmann et al. (1997) reported the results of domain deletion studies of the extracellular portion of FLT1. They showed that FLT1 domains 2 and 3 are necessary and sufficient for binding VEGF with near-native affinity and that domain 2 alone binds only 60-fold less tightly than wildtype.

He et al. (1999) described a mouse cDNA sequence encoding sFLT1 that is a potent antagonist to VEGF and showed its in vivo production. In situ hybridization and Northern blot analysis with probes specific for sFLT1 or FLT1 showed that the relative abundance of their mRNAs changed markedly in spongiotrophoblast cells in the placenta as gestation progressed. On day 11 of pregnancy, sFLT1 mRNA was undetectable but FLT1 was readily apparent, and by day 17 sFLT1 mRNA was abundant but FLT1 was barely detectable. The authors concluded that these data suggest a novel mechanism of regulation of angiogenesis by alternative splicing of FLT1 pre-mRNA.

Wulff et al. (2001) examined the effects of a soluble truncated form of FLT1, vascular endothelial growth factor trapA40 (VEGF trap), in a primate model to determine its ability to prevent the onset of luteal angiogenesis or intervene with the ongoing process. Marmosets were treated from the day of ovulation until luteal day 3 (prevention regimen) or on luteal day 3 for 1 day (intervention regimen). After both treatments, intense luteal endothelial proliferation was suppressed, a concomitant decrease in endothelial cell area confirmed the inhibition of vascular development, and a marked fall in plasma progesterone levels showed that luteal function was compromised. The authors concluded that the VEGF trap can prevent luteal angiogenesis and inhibit the established process with resultant suppression of luteal function; that luteal FLT mRNA expression is dependent upon VEGF; and that VEGF inhibition results in abortive increases in expression of VEGF, angiopoietin-2 (601922), and TIE2 (600221).

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 (192240) 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.

Autiero et al. (2003) reported that placental growth factor (PGF; 601121) regulates inter- and intramolecular cross-talk between the VEGF receptor tyrosine kinases FLT1 and FLK1. 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 (see 189800) women, Maynard et al. (2003) found increased 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.

In 120 preeclamptic women and 120 matched, normotensive controls, Levine et al. (2004) measured serum levels of the angiogenic factors sFLT1, PGF, and VEGF throughout pregnancy. During the last 2 months of pregnancy in the normotensive controls, the level of sFLT1 increased and the level of PGF decreased; these changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. At the onset of clinical disease, the mean serum level of sFLT1 in the preeclamptic women was significantly higher than that of controls with fetuses of similar gestational age (p less than 0.001). PGF levels were significantly lower in women who later had preeclampsia than in controls, beginning at 13 to 16 weeks of gestation (p = 0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with an increase in the sFLT1 level. Levine et al. (2004) concluded that increased levels of sFLT1 and reduced levels of PGF predict the subsequent development of preeclampsia.

Kaplan et al. (2005) demonstrated that bone marrow-derived hematopoietic progenitor cells that express VEGFR1 home to tumor-specific premetastatic sites and form cellular clusters before the arrival of tumor cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1-positive cells from the bone marrow of wildtype mice abrogated the formation of these premetastatic clusters and prevented tumor metastasis, whereas reconstitution with selected Id3 (600277)-competent VEGFR1-positive cells established cluster formation and tumor metastasis in Id3 knockout mice. Kaplan et al. (2005) also showed that VEGFR1-positive cells express VLA4, also known as integrin alpha-4-beta-1 (see 192975), and that tumor-specific growth factors upregulate fibronectin (135600), a VLA4 ligand, in resident fibroblasts, providing a permissive niche for incoming tumor cells. Conditioned media obtained from distinct tumor types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. Kaplan et al. (2005) concluded that their findings demonstrated a requirement for VEGFR1-positive hematopoietic progenitors in the regulation of metastasis, and suggested that expression patterns of fibronectin and VEGFR1-positive-VLA4-positive clusters dictate organ-specific tumor spread.

Ambati et al. (2006) showed that the cornea expresses soluble VEGF receptor-1, also known as SFLT1, and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference, or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 (see 609114) and Pax6 heterozygous mice (see 607108) and Pax6 heterozygous patients with aniridia (106210) are deficient in SFLT1, and recombinant Sflt1 administration restores corneal avascularity in corn1 and Pax6 heterozygous mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt1, whereas the avascular corneas of dugongs (also members of the order Sirenia), elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt1, indicating that it has a crucial, evolutionarily conserved role.

Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor A (VEGFA; 192240) or its receptor VEGFR1 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.

Using porcine aortic endothelial cells expressing human VEGFR2 (KDR), Sela et al. (2008) showed that both sFLT1 and sFLT1-14 inhibited VEGFR2 phosphorylation in a dose-dependent manner. Northern blot analysis of normal placenta showed that expression of soluble FLT1 transcripts increased progressively, and the increase was predominantly due to increased expression of sFLT1-14, which became the dominant transcript at the beginning of the second trimester. Expression of sFLT1-14 was further elevated in preeclamptic placentas. In situ hybridization showed that sFLT1-14 was expressed in syncytial knots characteristic of preeclamptic placentas, as well as in the many fewer syncytial knots formed in older normal placentas. Expression of sFLT1-14 was much lower in normal syncytiotrophoblasts. ELISA analysis detected sFLT1-14 in sera of preeclamptic women.

Stefater et al. (2011) showed that during development, retinal myeloid cells produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in retinal myeloid cells of the Wnt ligand transporter Wntless (611514) results in increased angiogenesis in the deeper layers. Stefater et al. (2011) also showed that mutation of Wnt5a (164975) and Wnt11 (603699) results in increased angiogenesis and that these ligands elicit retinal myeloid cell responses via a noncanonical Wnt pathway. Using cultured myeloid-like cells and retinal myeloid cell somatic deletion of Flt1, Stefater et al. (2011) showed that Flt1, a naturally occurring inhibitor of VEGF, is an effector of Wnt-dependent suppression of angiogenesis by retinal myeloid cells. Stefater et al. (2011) concluded that resident myeloid cells can use a noncanonical, Wnt-Flt1 pathway to suppress angiogenic branching.

Zhang et al. (2018) showed that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of neuropilin-1 (NRP1; 602069) and Vegfr1 (Flt1) renders mice resistant to diet-induced obesity. Absence of Nrp1 and Flt1 receptors increased Vegfa (192240) bioavailability and signaling through Vegfr2 (191306), inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by Vegfr2 and vascular endothelial cadherin (VE-cadherin; 601120) signaling inhibition rescued chylomicron transport in mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal VE-cadherin anchors prevented chylomicron uptake in wildtype mice.


Gene Structure

Sela et al. (2008) reported that the FLT1 gene contains at least 30 coding exons, all of which are included in the full-length FLT1 transcript. Use of alternative splice acceptor sites within introns 13 and 14 produces transcripts encoding the truncated soluble isoforms sFLT1 and sFLT1-14, respectively.


Mapping

Satoh et al. (1987) and Yoshida et al. (1987) mapped FLT to 13q12 by probing of DNA from a panel of human-mouse somatic cell hybrids and by in situ hybridization. By the isolation and analysis of a YAC containing the FLT1 and FLT3 (136351) genes, Imbert et al. (1994) confirmed their close physical linkage. FLT1 and FLT3 are linked in a head-to-tail configuration and are separated by about 150 kb. Imbert et al. (1994) found that the region contains 3 CpG islands, 2 of which were thought to correspond to FLT1 and FLT3 and the third to a putative, unidentified receptor-type tyrosine kinase (RTK) gene. They referred to studies performed by fluorescence in situ hybridization using the YAC as a probe.


Biochemical Features

Crystal Structure

Wiesmann et al. (1997) reported the crystal structure to 1.7-angstrom resolution of the complex between the receptor-binding domain of VEGF and FLT1 domain 2. The crystal structure of the complex between VEGF and the second domain of FLT1 shows domain 2 in a predominantly hydrophobic interaction with the 'poles' of the VEGF dimer. Based on this structure and on mutational data, Wiesmann et al. (1997) presented a model of VEGF bound to the first 4 domains of FLT1.

Role in Peripartum Cardiomyopathy Susceptibility

To test the idea that angiogenic signaling can cause cardiac dysfunction in pregnant women, Patten et al. (2012) studied women with preeclampsia (see 189800) who had compromised VEGF (192240) signaling due to high serum levels of antiangiogenic sFLT1. Cardiac function was evaluated noninvasively by measuring the myocardial performance index (MPI) and other indices of cardiac function with cardiac echocardiography. Women with preeclampsia had markedly increased serum levels of sFLT1 (p = 0.005), as previously shown by Levine et al. (2004). Notably, women with preeclampsia also had a markedly abnormal MPI and other indicators of cardiac diastolic dysfunction. The MPI correlated with levels of circulating sFLT1 (R = 0.59, p = 0.003). To test this idea directly, Patten et al. (2012) delivered sFLT1 systemically to pregnant mice by intravenous injection of adenoviruses expressing sFLT1 and examined MPI using high-resolution murine echocardiography. sFLT1 caused significant increases in MPI in these mice within 10 days. Patten et al. (2012) concluded that their data, taken together with published observations in patients receiving antiangiogenic therapies, strongly suggested that elevated sFLT1 causes cardiac dysfunction in women with preeclampsia.

Patten et al. (2012) collected plasma from women with peripartum cardiomyopathy (PPCM; 614670) 4 to 6 weeks postpartum and measured sFLT1 levels. sFLT1 levels usually return to normal within 48 to 72 hours after delivery. sFLT1 levels were elevated in a large subset of these PPCM patients (p = 0.002), remaining up to 5- to 10-fold higher than the levels of control participants. Postpartum sFLT1 levels can remain slightly higher in subjects with preeclampsia, but the levels found by Patten et al. (2012) in this subset of PPCM patients were notably higher. Thus, the findings were consistent with the idea that a substantial percentage of PPCM subjects have been exposed to preeclampsia, and that secretion of sFLT1 persists inappropriately postpartum. Among Harvard teaching hospitals included in the study by Patten et al. (2012), 33% of the last 75 cases of PPCM were associated with preeclampsia, markedly more than the population rate of 3 to 5%. The persisting extraplacental source of sFLT1 in the postpartum period was not known, and Patten et al. (2012) suggested that this source may include placental remnants, circulating mononuclear cells, or shed syncytial microparticles.

Patten et al. (2012) suggested that PPCM is caused by a 2-hit combination of, firstly, systemic antiangiogenic signals during late pregnancy, and, secondly, a host susceptibility marked by insufficient local proangiogenic defenses in the heart. The first hit explains why PPCM is a disease of the late gestational period, which is precisely when circulating antiangiogenic factors such as sFLT1 peak in pregnancy. The first hit is also worse in preeclampsia, which is characterized by markedly elevated sFLT1 levels. Patten et al. (2012) hypothesized a number of possible second hits, including abnormal PGC1-alpha (604517), myocarditis, immune activation, viral infection, and/or autoantibodies. Patten et al. (2012) concluded that their data supported the idea that PPCM is partly a 2-hit vascular disease due to imbalances in angiogenic signaling, and that antiangiogenic states such as preeclampsia or multiple gestation substantially worsen the severity of the disease. Their observations also suggested that proangiogenic therapies such as exogenous VEGF121, or removal of sFLT1 itself, may therefore be beneficial in PPCM.


Molecular Genetics

Fetal Loss in Placental Malaria

Placental malaria (PM; see 611162) is caused by P. falciparum-infected erythrocytes adhering to chondroitin sulfate A and sequestering in the maternal circulation of the placenta. The highest rates of PM and fetal loss are in first-time mothers. Muehlenbachs et al. (2008) showed that a dinucleotide repeat polymorphism approximately 3 kb downstream of the last exon of FLT1, rs3138582, was expressed within the FLT1 UTR. They classified dinucleotide repeat polymorphisms with more than 27 repeats as the long (L) allele and those with 27 repeats or less as the short (S) allele and investigated the relationship of FLT1 repeat length to poor outcomes caused by PM in Tanzanian mother-infant pairs. The newborn genotype distribution differed by birth order, with newborns of first-time mothers having a genotype distribution that was out of Hardy-Weinberg equilibrium during peak PM season, when significantly fewer SS homozygotes were born to these mothers. First-time mothers who were SS homozygous were more likely to report prior fetal loss than those with other genotypes. First-time mothers of SS homozygous offspring had higher plasma FLT1 levels during PM compared with first-time mothers of SL or LL offspring. Peripheral blood mononuclear cells stimulated with lipopolysaccharide showed increased expression of FLT1 mRNA and protein in infants with SS and SL genotypes than in those with LL genotype. Muehlenbachs et al. (2008) suggested that fetal genes such as FLT1 may modify maternal inflammation and may be under natural selection secondary to malaria.

Thyroid Cancer

Liu et al. (2008) explored a wide-range genetic basis for the involvement of genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC; see 188470). They found frequent copy gains of RTK genes including EGFR (131550), and VEGFR1, and in PIK3CA (171834) and PIK3CB (602925) in the P13K/Akt pathway. Copy number gain of VEGFR1 was found in 20 of 44 ATCs (46%) and 26 of 59 FTCs (44%). RTK gene copy gains were preferentially associated with phosphorylation of Akt, suggesting their dominant role in activating the P13K/Akt pathway. Liu et al. (2008) concluded that genetic alterations in the RTKs and P13K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.

Associations Pending Confirmation

For discussion of a possible association between variation near the FLT1 gene and risk of preeclampsia, see PEE1 (189800).


Animal Model

VEGF and its high-affinity binding receptors, the tyrosine kinases FLK1 and FLT1, are thought to be important for the development of embryonic vasculature. Studying transgenic mice in whom the Flk1 gene was disrupted, Shalaby et al. (1995) demonstrated a total failure of embryonic mice to develop blood vessels and failure of blood island formation in the yolk sac. Fong et al. (1995) reported that in mice Flt1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Transgenic mouse embryos homozygous for a targeted mutation in the Flt1 locus formed endothelial cells in both embryonic and extraembryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the blood islands of homozygous mice were abnormal, with angioblasts in the interior as well as on the periphery. Fong et al. (1995) suggested that the Flt1 signaling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.

Niida et al. (2005) stated that Csf1 (120420)-null mice are osteopetrotic and that those null for the Flt1 gene show mild osteoclast reduction without bone marrow suppression. They created double-knockout mice that exhibited severe osteoclast deficiency and did not have sufficient osteoclasts to form the bone marrow cavity. The cavity of double-knockout mice was gradually replaced with fibrous tissue, resulting in severe marrow hypoplasia and extramedullary hematopoiesis. The number of osteoblasts was also decreased. Niida et al. (2005) concluded that FLT1 and CSF1 receptors play predominant roles in osteoclastogenesis and the maintenance of bone marrow function.

Using a transgenic mouse model of rheumatoid arthritis (RA; 180300) and antibodies to Vegf, Vegfr1, and Vegfr2, De Bandt et al. (2003) found that synovial cells from arthritic joints expressed all 3 proteins. Treatment with anti-Vegfr1 strongly attenuated the disease throughout the study period, whereas anti-Vegf transiently delayed disease onset and anti-Vegfr2 treatment had no effect. Histologic analysis showed that treatment with a VEGFR1 tyrosine kinase inhibitor nearly abolished the disease. De Bandt et al. (2003) concluded that VEGF is a key factor in pannus development, acting through the VEGFR1 pathway, and they proposed that VEGFR1 inhibitors may be useful in the treatment of RA.

In laser-injury studies in mice, Nozaki et al. (2006) observed that injury-induced choroidal neovascularization (CNV) was increased by excess Vegf before injury but was suppressed by Vegf after injury. This effect was mediated via Vegfr1 activation and Vegfr2 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.

Since Flt1 is a decoy receptor for vascular endothelial growth factor (VEGF; 192240), both homozygous (Flt1 -/-) and heterozygous (Flt1 +/-) Flt1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. In addition to its presence in muscle, dystrophin (300377) is also found in vasculature, and its absence results in vascular deficiency and abnormal blood flow. To create a mouse model of Duchenne muscular dystrophy (DMD; 310200) with increased vasculature, Verma et al. (2010) crossed mdx mice with Flt1 knockout mice. Flt1 +/- and mdx:Flt1 +/- adult mice displayed a developmentally increased vascular density in skeletal muscle compared with wildtype and mdx mice, respectively. The mdx:Flt1 +/- mice showed improved muscle histology compared with mdx mice, with decreased fibrosis, calcification, and membrane permeability. Functionally, the mdx:Flt1 +/- mice had an increase in muscle blood flow and force production compared with mdx mice. Because utrophin (128240) is upregulated in mdx mice and can compensate for the lacking function of dystrophin, Verma et al. (2010) created a triple-mutant mouse (mdx:utrophin -/-:Flt1 +/-). The mdx:utrophin -/-:Flt1 +/- mice also displayed improved muscle histology and significantly higher survival rates compared with mdx:utrophin -/- mice, which showed more severe muscle phenotypes than mdx mice. Verma et al. (2010) suggested that increasing the vasculature in DMD may ameliorate the histologic and functional phenotypes associated with this disease.


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Contributors:
Ada Hamosh - updated : 09/24/2018
George E. Tiller - updated : 06/22/2017
Ada Hamosh - updated : 5/30/2012
Ada Hamosh - updated : 7/1/2011
Patricia A. Hartz - updated : 7/15/2009
John A. Phillips, III - updated : 5/7/2009
Paul J. Converse - updated : 4/23/2009
Ada Hamosh - updated : 4/15/2008
Ada Hamosh - updated : 12/6/2006
Marla J. F. O'Neill - updated : 7/10/2006
Ada Hamosh - updated : 5/26/2006
Paul J. Converse - updated : 4/11/2006
Patricia A. Hartz - updated : 3/10/2006
Marla J. F. O'Neill - updated : 2/18/2005
Ada Hamosh - updated : 6/17/2003
Ada Hamosh - updated : 2/21/2003
John A. Phillips, III - updated : 3/12/2002
John A. Phillips, III - updated : 6/28/2001
Stylianos E. Antonarakis - updated : 12/19/1997
Jennifer P. Macke - updated : 6/6/1997

Creation Date:
Victor A. McKusick : 9/2/1987

Edit History:
alopez : 09/24/2018
alopez : 09/06/2017
carol : 06/27/2017
alopez : 06/22/2017
alopez : 12/03/2013
alopez : 6/4/2012
terry : 5/30/2012
alopez : 7/6/2011
terry : 7/1/2011
carol : 5/20/2010
mgross : 7/20/2009
mgross : 7/17/2009
mgross : 7/17/2009
terry : 7/15/2009
alopez : 5/7/2009
alopez : 5/7/2009
alopez : 5/7/2009
mgross : 5/4/2009
mgross : 5/4/2009
terry : 4/23/2009
alopez : 5/16/2008
alopez : 5/15/2008
terry : 4/15/2008
alopez : 12/13/2006
terry : 12/6/2006
wwang : 7/11/2006
terry : 7/10/2006
alopez : 6/7/2006
terry : 5/26/2006
mgross : 5/1/2006
terry : 4/11/2006
wwang : 3/27/2006
terry : 3/10/2006
wwang : 3/1/2005
terry : 2/18/2005
alopez : 7/28/2003
alopez : 6/18/2003
terry : 6/17/2003
terry : 6/17/2003
alopez : 2/25/2003
terry : 2/21/2003
alopez : 3/12/2002
alopez : 10/30/2001
cwells : 7/3/2001
cwells : 6/28/2001
alopez : 5/7/2001
terry : 11/13/1998
carol : 7/29/1998
carol : 12/19/1997
alopez : 9/10/1997
alopez : 9/10/1997
jamie : 10/30/1996
mark : 7/5/1995
terry : 10/31/1994
supermim : 3/16/1992
carol : 1/3/1991
supermim : 3/20/1990
carol : 3/9/1990