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This term has multiple meanings:
(-1-) viral EGF. See: VGF.
Copyright © 2012 by H IBELGAUFTS. All rights reserved.
(-2-) [vascular endothelial growth factor; vasculo-endothelial growth factor] also: VEG/PF (vascular endothelial growth factor/vascular permeability factor) or VEGF-1 [vascular endothelial growth factor-1].
GD-VEGF (glioma-derived vascular endothelial growth factor);
Mouse sarcoma 180-derived growth factor;
Vascular endothelial cell proliferation factor;
VPF (vascular permeability factor).
See also: individual entries for further information.
VEGF has been isolated from bovine pituitaries. The protein is produced also by murine neuroblastoma cell lines and a plethora of other tumor cells, tumors, and normal cell types, including macrophages, lung epithelial cells, kidney epithelial cells, follicular cell in the pituitary, corpus luteum cells, aortic smooth muscle cells. For snake venom VEGF species see also: svVEGF, VEGF-F, TfsvVEGF, ICPP.
VEGF is called also VEGF-A, following the identification of several VEGF-related factors (VEGF-B, VEGF-C, VEGF-D, VEGF-E). For a related factor see also: GD-VEGF. A considerably larger form of VEGF has been described as L-VEGF.
VEGF is a homodimeric heavily glycosylated protein of 46-48 kDa (24 kDa subunits). Glycosylation is not required, however, for biological activity. The subunits are linked by disulfide bonds. The human factor occurs in several molecular variants of 111 (VEGF-111), 121 (VEGF-121, VEGF-121b), 145 (VEGF-145, VEGF-145b), 148 (VEGF-148), 162 (VEGF-162), 165 (VEGF-165; VEGF-165b), 183 (VEGF-183, VEGF-183b), 189 (VEGF-189, VEGF-189b), 206 (VEGF-206) amino acids, arising by alternative splicing of the mRNA. By convention, the form VEGF-Axxx (or VEGF-xxx) is used for variants that promote angiogenesis. Designations with a suffixed letter 'b' such as VEGF-Axxxb (or VEGF-xxxb) are splice variants that have anti-angiogenic activities (Woolard et al, 2004) ( for further explanations and nomenclature see: VEGF-A). For a peptide with anti-angiogenic activity derived from VEGF exon 6 see: 6a-P.
The splice forms of VEGF differ in their interaction with heparan sulfate proteoglycans and also vary in their individual bioactivities, depending upon the receptor utilized and individual receptor affinities.
The 165 amino acid form of the factor (VEGF-165) is the most common form in most tissues. The VEGF-121, VEGF-165, and VEGF-189 forms appear to be the more abundant isoforms and are usually produced simultaneously by (Neufeld et al, 1999). Kaposi sarcomas express VEGF-121 and VEGF-165. The 189 amino acid variant of VEGF (VEGF-189) is identical with VPF (vascular permeability factor).
VEGF-121 and VEGF-165 are soluble secreted forms of the factor while VEGF-189 and VEGF-206 are mostly bound to heparin-containing proteoglycans in the cell surface or in the basement membrane (see also: extracellular matrix). The bioavailability of VEGF is regulated probably at the genetic level by alternative splicing that determines whether VEGF will be soluble or incorporated into a biological reservoir and also through proteolysis following plasminogen activation.
Rat and bovine VEGF are one amino acid shorter than the human factor, and the bovine and human sequences show a homology of 95 %.
VEGF is not related with fibroblast growth factors (see: FGF) and only displays limited homology (18 %) to the beta chain of PDGF. However, the positions of all eight cysteine residues are conserved in VEGF and PDGF.
In contrast to other factors mitogenic for endothelial cells such as aFGF, bFGF and PDGF VEGF is synthesized as a precursor containing a typical hydrophobic secretory signal sequence of 26 amino acids. Glycosylation is not required for efficient secretion of VEGF.
For a VEGF-related factor see also: VRF.
The rat GS-9L glioma cell line has been shown to produce heterodimers composed of VEGF and PlGF subunits in addition of VEGF and PlGF homodimers.
For virus-encoded proteins that may act like VEGF mimics see orf virus (see also: Virokine).
The human gene has a length of approximately 12 kb and contains eight exons. Four species of mRNA encoding VEGF have been identified and found to be expressed in a tissue-specific manner. They arise from differential splicing with the 165 amino acid form of VEGF lacking sequences encoded by exon 6 and the 121 amino acid form lacking exon 6 and 7 sequences. The VEGF gene maps to human chromosome 6p12-p21.
A high-affinity glycoprotein receptor of 170-235 kDa is expressed on vascular endothelial cells. The interaction of VEGF with heparin-like molecules of the extracellular matrix is required for efficient receptor binding. Protamine sulfate and suramin are capable of replacing the receptor-bound factor. The high-affinity receptor for VEGF, now known as VEGFR1, has been identified as the gene product of the flt-1. Another receptor for VEGF, now known as VEGFR2, is KDR, also known as flk-1. A factor that competes with the 165 amino acid form of VEGF for receptor binding is PlGF (placenta growth factor). A third receptor type, VEGFR3 is known also as flt-4. An isoform-specific receptor for VEGF-165 (VEGF-165R) has been identified as human Neuropilin-1.
The binding of VEGF to Alpha-2-Macroglobulin inhibits its receptor binding ability, indicating that this protein may function as a VEGF removal and inactivation factor. Heparin and heparan sulfate, but not other glycosaminoglycans such as chondroitin sulfate, efficiently inhibit the binding of VEGF to Alpha-2-Macroglobulin.
For a designer binding protein affecting VEGF binding to its receptor, KDR, see: GFB-111.
The biological activities of VEGF are not species-specific. The different isoforms of VEGF have different properties in vitro and this may apply also to their in vivo functions.
VEGF is a highly specific mitogen for vascular endothelial cells. In vitro the two shorter forms of VEGF stimulates the proliferation of macrovascular endothelial cells. VEGF does not appear to enhance the proliferation of other cell types. VEGF significantly influence vascular permeability and is a strong angiogenic protein in several bioassays (see also: Angiogenesis) and probably also plays a role in neovascularisation under physiological conditions. A potent synergism between VEGF and bFGF in the induction of angiogenesis has been observed. It has been suggested that VEGF released from smooth muscle cells and macrophages may play a role in the development of arteriosclerotic diseases.
In endothelial cells VEGF induces the synthesis of von Willebrand factor. It is also a potent chemoattractant for monocytes (see also: Chemotaxis) and thus has procoagulatory activities. In microvascular endothelial cells VEGF induces the synthesis of plasminogen activator and plasminogen activator inhibitor type 1. VEGF also induces the synthesis of the metalloproteinase, interstitial collagenase, which degrades interstitial collagen type 1, collagen type 2, and collagen type 3 under normal physiological conditions.
In several organs the expression of VEGF appears to be regulated during development. VEGF plays a role in the development and function of primate follicles and the ovarian corpus luteum, supporting the proliferation of blood vessels. The differentiation of adipocytes, of pheochromocytomas, and myocytes is accompanied by the controlled expression of VEGF.
Borgstrom et al (1996) have shown that treatment of immunodeficient mice (nude and beige nude/xid) carrying a transplanted human rhabdomyosarcoma cell line A673) with a monoclonal antibody specific for VEGF completely inhibits neovascularization of the microtumors and suppresses their growth.
TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES
The biological consequences of a VEGF flt-1 or flk-1 receptor gene disruption have been studied in knock-out mice generated from ES cells carrying a targeted deletion of the gene. Transgenic mutant mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5.
Transgenic mutant mice homozygous for a deletion of the VEGF gene have been studied also. Loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12. Angiogenesis and blood-island formation is impaired, resulting in several developmental anomalies. In addition, embryonic stem cells lacking the VEGF gene exhibit a dramatically reduced ability to form tumors in nude mice.
DETECTION AND ASSAY METHODS
VEGF can be assayed by an immunofluorometric test. An alternative and entirely different detection method is RT-PCR quantitation of cytokines. For further information see also subentry "Assays" in the reference section. For further information on assays for cytokines see also: bioassays, cytokine assays.
CLINICAL USE AND SIGNIFICANCE
VEGF is important probably in the pathophysiology of neuronal and other tumors, probably functioning as a potent promoter of angiogenesis for human gliomas. Its synthesis is induced also by hypoxia. The extravasation of cells observed as a response to VEGF may be an important factor determining the colonization of distant sites. Due to its influences on vascular permeability VEGF may be involved also in altering blood-brain-barrier functions under normal and pathological conditions. The production of VPF in human malignant glioma cells expressing EGF receptors is significantly increased by EGF. VEGF released by glioma cells in situ most likely accounts for the clinical features of glioblastoma multiforme tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.
VEGF secreted from the stromal cells may be responsible for the proliferation of endothelial cells in capillary hemangioblastomas, which are composed of abundant microvasculature and primitive angiogenic elements represented by stromal cells. The production and secretion of VEGF by human retinal pigment epithelial cells may be important in the pathogenesis of ocular neovascularization.
The treatment of nude mice (see also: Immunodeficient mice) carrying transplanted human rhabdomyosarcoma, glioblastoma or leuomyosarcoma cells with antibodies directed against VEGF inhibits tumor growth. The observation that the growth of these tumors in vitro remains unaffected by the antibody demonstrates that the inhibition of angiogenesis in the transplanted tumors is one of the major causes of tumor growth suppression. The expression of VEGF-121 or VEGF-165 in CHO cells confers the ability to form tumors in nude mice.
See REFERENCES for entry VEGF.
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