Vascular endothelial growth factor
From Wikipedia, the free encyclopedia
vascular endothelial growth factor
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Identifiers | |
Symbol(s) | VEGF |
Entrez | 7422 |
OMIM | 192240 |
RefSeq | NM_001025366 |
UniProt | P15692 |
Other data | |
Locus | Chr. 6 p21-p12 |
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity is restricted mainly to cells of the vascular endothelium, although it does have effects on a limited number of other cell types (e.g. stimulation monocyte/macrophage migration). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF also enhances microvascular permeability and is sometimes referred to as vascular permeability factor.
The broad term 'VEGF' covers a number of proteins that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene. The different VEGF splice variants are referred to by the number of amino acids they contain (in humans: VEGF121, VEGF145, VEGF165, VEGF189, VEGF206; the rodent orthologs of these proteins contain one less amino acid). These proteins differ by the presence or absence of short C-terminal domains encoded by exons 6a, 6b and 7 of the VEGF gene. These domains have important functional consequences for the VEGF splice variants as they mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the VEGF signaling receptors (VEGFRs).
The VEGF splice variants are released from cells as glycosylated disulfide-bonded homodimers. Structurally VEGF belongs to the PDGF family of cystine-knot growth factors. Subsequently, several closely-related proteins were discovered (Placenta growth factor (PlGF), VEGF-B, VEGF-C and VEGF-D) which together comprise the VEGF sub-family of growth factors. VEGF is sometimes referred to as VEGF-A to differentiate it from these related growth factors. A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F).
All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated through transphosphorylation. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3), however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.
VEGF production can be induced in cells that are not receiving enough oxygen. When a cell is deficient in oxygen, it produces HIF, Hypoxia Inducible Factor, a transcription factor. HIF stimulates the release of VEGF, among other functions (including modulation of erythropoeisis). Circulating VEGF then binds to VEGF Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to angiogenesis.
VEGF has been implicated with poor prognosis in breast cancer. Numerous studies show a decreased OS and DFS in those tumors overexpressing VEGF. The overexpression of VEGF may be an early step in the process of metastasis, a step that is involved in the "angiogenic" switch. Although VEGF has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.
VEGF is also released in rheumatoid arthritis in response to TNF-α, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).
VEGF is also important in diabetic retinopathy. The microcirculatory problems in the retina of people with diabetes can cause retinal ischaemia, which results in the release of VEGF. VEGF may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight.
Once released, VEGF may elicit several responses. It may cause a cell to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of cancer. The first anti-VEGF drug, a monoclonal antibody named bevacizumab, was approved in 2004.
Current studies show that VEGFs are not the only promoters of angiogenesis. In particular FGF2 and HGF are potent angiogenic factors.