VEGF

What is VEGF?

Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate.

VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) to bypass blocked vessels.

When VEGF is overexpressed, 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 bevacizumab can inhibit VEGF and control or slow those diseases.

VEGF is a sub-family of growth factors, specifically 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).

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VEGF Classification

The most important member is VEGF-A. Other members are Placenta growth factor (PlGF), VEGF-B, VEGF-C and VEGF-D. The latter ones were discovered later than VEGF-A, and, before their discovery, VEGF-A was called just VEGF.

A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F).

Comparison
TypeFunction
VEGF-A 
  • Angiogenesis
    • ↑ Migration of endothelial cells
    • ↑ mitosis of endothelial cells
    • ↑ Methane monooxygenase activity
    • ↑ αvβ3 activity
    • creation of blood vessel lumen
    • creates fenestrations
    • Chemotactic for macrophages and granulocytes
    • Vasodilation (indirectly by NO release)
VEGF-BEmbryonic angiogenesis
VEGF-CLymphangiogenesis
VEGF-DNeeded for the development of lymphatic vasculature surrounding lung bronchioles
PlGFImportant 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.

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VEGF Mechanism

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), which mediates lymphangiogenesis.

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VEGF Production

VEGFxxx 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 VEGFxxx, among other functions (including modulation of erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to angiogenesis.

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.

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VEGF Clinical Significance

VEGFxxx has been implicated with poor prognosis in breast cancer. Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that is involved in the "angiogenic" switch. Although VEGFxxx has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.

VEGFxxx is also released in rheumatoid arthritis in response to TNF-α, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).

VEGFxxx is also important in diabetic retinopathy (DR). The microcirculatory problems in the retina of people with diabetes can cause retinal ischaemia, which results in the release of VEGFxxx, and a switch in the balance of pro-angiogenic VEGFxxx isoforms over the normally expressed VEGFxxxb isoforms. VEGFxxx may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight.

VEGFxxx plays a role in the disease pathology of the wet form age-related macular degeneration (AMD), which is the leading cause of blindness for the elderly of the industrialized world. The vascular pathology of AMD shares certain similarities with diabetic retinopathy, although the cause of disease and the typical source of neovascularization differes between the two diseases.

VEGF-D serum levels are significantly elevated in patients with angiosarcoma.

Once released, VEGFxxx 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. Approximately 10-15% of patients benefit from bevacizumab therapy; however, biomarkers for bevacizumab efficacy are not yet known.

Current studies show that VEGFs are not the only promoters of angiogenesis. In particular FGF2 and HGF are potent angiogenic factors.

Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.

In the kidney, increased expression of VEGFxxx in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria.

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Anti-VEGF Therapies

Anti-VEGF therapies are important in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab (Avastin), antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: lapatinib (Tykerb), sunitinib (Sutent), sorafenib (Nexavar), axitinib, and pazopanib.

Both antibody-based compounds are commercialized. The first three orally available compounds are commercialized, as well. The latter two are in clinical trials, the results of which were presented (June 7) at the American Society of Clinical Oncology meeting.

Bergers and Hanahan concluded in 2008 that anti-VEGF drugs can show therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. But, "the benefits are at best transitory and are followed by a restoration of tumour growth and progression."

AZ2171, a multi-targeted tyrosine kinase inhibitor has been shown to have antiedema effects by reducing the permeability and aiding in vascular normalization.

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