VASCULAR ENDOTHELIAL GROWTH FACTOR; VEGF
Angiogenesis (blood vessel growth), lymphangiogenesis (lymph system growth) are all intrinsically connected with lymphedema and share many of the same genes. We have several pages on both processes.
May 23, 2008
|VASCULAR ENDOTHELIAL GROWTH FACTOR; VEGF|
Alternative titles; symbolsVEGFAGene map locus 6p12
Many polypeptide mitogens, such as basic fibroblast growth factor (FGFB; 134920) and platelet-derived growth factors (173430, 190040), are active on a wide range of different cell types. In contrast, vascular endothelial growth factor is a mitogen primarily for vascular endothelial cells. It is, however, structurally related to platelet-derived growth factor.
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.
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.
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.
VEGF, a homodimeric glycoprotein of relative molecular mass 45,000, 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, 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.
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. See also VEGFB (601398). A third member of this family may be the ligand of the related FLT4 receptor (136352) 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 (VEGFR2; 191306) 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.
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.
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.
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 IFG1 (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, 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 (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.
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.
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 (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 (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 and higher levels of vascular endothelial growth factor (VEGF; 192240) might be related to the angiogenesis in proliferative 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 (-634C-G; 192240.0001) differed significantly between type 2 diabetic patients without retinopathy and those with any retinopathy, and the C allele was significantly associated with the presence of 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 (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.
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.
Lambrechts et al. (2003) followed up on the observation that reduced expression of VEGFA 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) predisposes the mice to adult-onset progressive motoneuron degeneration, with many neuropathologic and clinical signs reminiscent of human ALS. In a metaanalysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, they found that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G 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 indicated that VEGF 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.
Carmellet 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 mid-gestation. 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).
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.
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 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% confidence interval 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.
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
Victor A. McKusick : 9/11/1991
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
For Further Information of VEGF
|Vascular Endothelial Growth Factor (VEGF) & Receptors|
|Cell Signaling & Neuroscience|
Pub Med - Links page for VEGF
Lymphedema People Angiogenesis Related Pages:
Angiogenesis and Cancer
Angiogenesis and Cancer Control
Angiogenesis Inhibitors and Cancer
Lymphedema People Lymphangiogenesis Related Pages:
Lymphatic Vessels and Its Importance in the Setting of Malignancy
Lymphangiogenesis Lymphedema and Cancer
Lymphangiogenesis and Gastric Cancer
Lymphangiogenesis in Head and Neck Cancer
Lymphangiogenesis and Kaposi's Sarcoma VEGF-C
Lymphangiogenesis in Wound Healing
A model for gene therapy of human hereditary lymphedema
VEGFR-3 Ligands and Lymphangiogenesis (1)
VEGFR-3 Ligands and Lymphangiogenesis (2)
VEGFR-3 Ligands and Lymphangiogenesis (3)
Vascular Endothelial Growth Factor; VEGF
VEGF-D is the strongest angiogenic and lymphangiogenic effector
Inhibition of Lymphatic Regeneration by VEGFR3
VEGFR3 and Metastasis in Prostate Cancer
Lymphedema People Genetics, Research, Lymphangiogenesis, Angiogenesis Forum
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Lymphedema People - Support Groups
The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.
No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.
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MEN WITH LYMPHEDEMA
If you are a
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Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.
Disorders Support Group @ Yahoo Groups
While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.
Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.
For our Google fans, we have just created this online support group in Google Groups:
Group email: All-About-Lymphedema@googlegroups.com
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you seen our new “Wiki”
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