Vascular Endothelial Growth Factor

Vascular Endothelial Growth Factor (VEGF ) is an important signaling molecule that exerts its effect in both vasculogenesis ( the de novo formation of the embryonic circulatory system ), as well as in angiogenesis. As the name implies, this factor stimulates mainly vascular endothelium, but also has effects on other cells (e.g., stimulation of migration of monocytes and macrophages). In vitro, VEGF stimulates the division and migration of endothelial cells. There are seven different forms of known ( AF and PlGF ), VEGF.

The term VEGF describes a family of proteins which have different properties. Was first discovered VEGF -A, then the factors VEGF-B and PlGF ( Placental Growth Factor ) and VEGF-C and VEGF-D have (both important for the formation of lymphatic vessels ) detected. Besides that, there, the related viral homologues ( VEGF -E) and the present in snake venom VEGF -F.

VEGF-A

In adult VEGF-A is found in nearly all vascular tissue, and it is thought that it is necessary for vascular homeostasis. The gene encoding VEGF-A can be produced by alternative splicing produce different variants of the protein are of different length. As previously, the variants of VEGF - A121, VEGF -A138, VEGF- A145, VEGF- A162, VEGF- A165, VEGF- A165b, VEGF- A189 VEGF - A206 have been described in humans (the numbers correspond to the number of amino acids in each protein ).

These proteins will be differentiated only by short domains at the C -terminus, but this has a major impact on their biological function and their interaction with heparan sulfates controls and the co- receptor neuropilin.

Function

All members of the VEGF family cause a cellular response by bind to a tyrosine kinase, VEGF receptor ( VEGFR ) and then forward the extracellular signal into the cell. There are three receptors ( VEGFR 1-3), with different affinities observed. VEGF-A binds only to the receptor type 1 and 2, while PlGF and VEGF-B bind only to the receptor type 1 and bind VEGF-C and VEGF-D, only the receptors type 2, and 3 of VEGF -E and F both to the receptors type 2 receptors dimerize after they have bound VEGF, and then phosphorylate each other. Order to be active and pass the signal on.

The production of VEGF is stimulated when cells are not getting enough oxygen. In this case, cells produce hypoxia -induced factors that lead to the secretion of VEGF and finally to angiogenesis.

In the vessel wall VEGF stimulates the production of nitric oxide (NO ), this in turn leads to vasodilation ( vasodilation ) and for lowering the blood pressure.

Medical importance

Increased expression of VEGF-A is found in a number of tumors. In addition, the interaction between VEGF and the VEGF receptor in the kidney plays an important role in the development of the organ and in the maintenance of the filtration barrier.

The monoclonal antibody Bevacizumab binds to VEGF, thus inhibiting the formation of new vessels (angiogenesis). Bevacizumab has been successfully used in phase III trials against colon cancer, lung cancer and breast cancer. In Phase II clinical trials of bevacizumab was used in the treatment of pancreatic cancer, kidney cancer and prostate cancer. Side effects are bleeding, ulcers in the gastrointestinal tract and kidney damage from high blood pressure and protein in the urine. Ranibizumab is a fragment of the same antibody. It is used to treat the moisture macular degeneration, a common eye disease leading to blindness, accompanied in many cases with neovascularization used. Also, bevacizumab is used off-label for this indication.

The tyrosine kinase inhibitors sunitinib, sorafenib and vatalanib inhibit inter alia, the VEGF receptor. Sunatinib and sorafenib be used in the treatment of advanced renal cancer, vatalanib, inter alia, in the treatment of cancer.

VEGF Trap is a recombinant fusion protein in which the binding domain of the soluble VEGF receptor to the Fc fragment of immunoglobulin G in combination. VEGF Trap binds all isoforms of VEGF. It is currently being tested in the treatment of cancer and in the treatment of macular degeneration humidities.

Pegaptanib is an aptamer that specifically binds to VEGF -A. It is approved for the treatment of macular degeneration humidities.

In renal VEGF is responsible for maintaining the integrity of the capillary endothelial fenestrated. In pregnancy, VEGF can be inhibited by the soluble VEGF receptor ( sFlt1 ). This is formed in the placenta and reach the blood in the kidney. Consequence of the reduced VEGF activity include swelling of the endothelial cells in the glomeruli, which ultimately lead to the symptoms of pre-eclampsia. In cancer patients, an anti -VEGF treatment of thrombotic microangiopathy proteinuria and lead.