vascular endothelial growth factor vascular endothelial growth factor vascular endothelial growth factor (vegf, /vɛdʒˈɛf/), originally known as vascular permeability factor (vpf), is a signal protein produced by many cells that stimulates the formation of blood vessels. to be specific, vegf is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. they are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). it is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions. serum concentration of vegf is high in bronchial asthma and diabetes mellitus. vegf's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. it can contribute to disease. solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express vegf are able to grow and metastasize. overexpression of vegf can cause vascular disease in the retina of the eye and other parts of the body. drugs such as aflibercept, bevacizumab, ranibizumab, and pegaptanib can inhibit vegf and control or slow those diseases. history in 1970, judah folkman et al. described a factor secreted by tumors causing angiogenesis and called it tumor angiogenesis factor. in 1983 senger et al. identified a vascular permeability factor secreted by tumors in guinea pigs and hamsters. in 1989 ferrara and henzel described an identical factor in bovine pituitary follicular cells which they purified, cloned and named vegf. a similar vegf alternative splicing was discovered by tischer et al. in 1991. between 1996 and 1997, christinger and de vos obtained the crystal structure of vegf, first at 2.5 å resolution and later at 1.9 å. fms-like tyrosine kinase-1 (flt-1) was shown to be a vegf receptor by ferrara et al. in 1992. the kinase insert domain receptor (kdr) was shown to be a vegf receptor by terman et al. in 1992 as well. in 1998, neuropilin 1 and neuropilin 2 were shown to act as vegf receptors. classification crystal structure of vammin, a vegf-f from a snake venom in mammals, the vegf family comprises five members: vegf-a, placenta growth factor (pgf), vegf-b, vegf-c and vegf-d. the latter members were discovered after vegf-a; before their discovery, vegf-a was known as vegf. a number of vegf-related proteins encoded by viruses (vegf-e) and in the venom of some snakes (vegf-f) have also been discovered. vegf family typefunction vegf-a angiogenesis ↑ migration of endothelial cells ↑ mitosis of endothelial cells ↑ matrix metalloproteinase activity ↑ αvβ3 activity ↑ migration and proliferation of astrocytes creation of blood vessel lumen creates fenestrations chemotactic for macrophages and granulocytes vasodilation (indirectly by no release) lymphangiogenesis vegf-b embryonic angiogenesis (myocardial tissue, to be specific) vegf-c lymphangiogenesis vegf-d needed for the development of lymphatic vasculature surrounding lung bronchioles plgf important for vasculogenesis, also needed for angiogenesis during ischemia, inflammation, wound healing, and cancer. activity of vegf-a, as its name implies, has been studied mostly on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g., stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells). in vitro, vegf-a has been shown to stimulate endothelial cell mitogenesis and cell migration. vegf-a is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor. isoforms schematic representation of the different isoforms of human vegf there are multiple isoforms of vegf-a that result from alternative splicing of mrna from a single, 8-exon vegfa gene. these are classified into two groups which are referred to according to their terminal exon (exon 8) splice site: the proximal splice site (denoted vegfxxx) or distal splice site (vegfxxxb). in addition, alternate splicing of exon 6 and 7 alters their heparin-binding affinity and amino acid number (in humans: vegf121, vegf121b, vegf145, vegf165, vegf165b, vegf189, vegf206; the rodent orthologs of these proteins contain one fewer amino acids). these domains have important functional consequences for the vegf splice variants, as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). in addition, inclusion or exclusion of exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (hspgs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the vegf receptors (vegfrs). recently, vegf-c has been shown to be an important inducer of neurogenesis in the murine subventricular zone, without exerting angiogenic effects. mechanism types of vegf and their vegf receptors. 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, although to different sites, times, and extents. 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). vegf-c and vegf-d, but not vegf-a, are ligands for a third receptor (vegfr-3/flt4), which mediates lymphangiogenesis. the receptor (vegfr3) is the site of binding of main ligands (vegfc and vegfd), which mediates perpetual action and function of ligands on target cells. vascular endothelial growth factor-c can stimulate lymphangiogenesis (via vegfr3) and angiogenesis via vegfr2. vascular endothelial growth factor-r3 has been detected in lymphatic endothelial cells in cl of many species, cattle, buffalo and primate. in addition to binding to vegfrs, vegf binds to receptor complexes consisting of both neuropilins and vegfrs. this receptor complex has increased vegf signalling activity in endothelial cells (blood vessels). neuropilins (nrp) are pleiotropic receptors and therefore other molecules may interfere with the signalling of the nrp/vegfr receptor complexes. for example, class 3 semaphorins compete with vegf165 for nrp binding and could therefore regulate vegf-mediated angiogenesis. expression vegf-a production can be induced in a cell that is 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-a, among other functions (including modulation of erythropoiesis). circulating vegf-a then binds to vegf receptors on endothelial cells, triggering a tyrosine kinase pathway leading to angiogenesis. the expression of angiopoietin-2 in the absence of vegf leads to endothelial cell death and vascular regression. conversely, a german study done in vivo found that vegf concentrations actually decreased after a 25% reduction in oxygen intake for 30 minutes. hif1 alpha and hif1 beta are constantly being produced but hif1 alpha is highly o2 labile, so, in aerobic conditions, it is degraded. when the cell becomes hypoxic, hif1 alpha persists and the hif1alpha/beta complex stimulates vegf release. the combined use of microvesicles and 5-fu resulted in enhanced chemosensitivity of squamous cell carcinoma cells more than the use of either 5-fu or microvesicle alone. in addition, down regulation of vegf gene expression was associated with decreased cd1 gene expression. clinical significance