Vascular endothelial growth factor

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Vascular endothelial growth factor ( VEGF ), originally known as the vascular permeability factor ( VPF ), is a signal protein produced by cells that stimulate the formation of blood vessels. To be more specific, VEGF is a sub-family of growth factors, a family of growth factors derived from platelets from cystine-knot growth factor. They are important signaling proteins involved in both vasculogenesis ( de novo formation of embryonic circulatory systems) and angiogenesis (growth of blood vessels from pre-existing blood vessels).

This is part of the system that returns oxygen supply to the tissues when blood circulation is not adequate as in hypoxic conditions. High serum VEGF concentrations in bronchial asthma and diabetes mellitus. The normal function of VEGF is to create new blood vessels during embryonic development, new blood vessels after injury, muscle after exercise, and new vessels (collateral circulation) to bypass clogged vessels.

When VEGF is overexpressed, it can contribute to the disease. Solid cancers can not grow beyond the limited size without adequate blood supply; cancer that can express VEGF can grow and metastasize. Excessive expression of VEGF can cause vascular disease in the retina of the eyes and other parts of the body. Drugs such as aflibercept, bevacizumab, ranibizumab and sodium Pegaptanib (Macugen) can inhibit VEGF and control or slow the disease.

Video Vascular endothelial growth factor

History

VEGF was first identified in guinea pigs, hamsters, and rats by Senger et al. in 1983. It was purified and cloned by Ferrara and Henzel in 1989. Alternative VEGF splicing was invented by Tischer et al. in 1991. Between 1996 and 1997, Christinger and De Vos obtained the VEGF crystal structure, first at 2.5 ÃÆ'... resolution and then at 1.9 ÃÆ'â € |.

Fms-like tyrosine kinase-1 (flt-1) proved to be a VEGF receptor by Ferrara et al. in 1992. The domain receptor insert kinase (KDR) proved to be a VEGF receptor by Terman et al. in 1992 as well. In 1998, neuropilin 1 and neuropilin 2 proved to act as VEGF receptors.

Maps Vascular endothelial growth factor

Classification

The VEGF family consists of five mammalian members: VEGF-A, placental growth factor (PGF), VEGF-B, VEGF-C and VEGF-D. The latter was found after VEGF-A, and, prior to their discovery, VEGF-A was simply called VEGF. A number of VEGF-associated proteins encoded by the virus (VEGF-E) and in some snake venom (VEGF-F) have also been found.

VEGF-A activity, as the name suggests, has been extensively studied in vascular endothelium cells, although it has effects on a number of other cell types (eg, monocyte stimulation/macrophage migration, neurons, cancer cells, renal epithelial cells). In vitro, VEGF-A has been shown to stimulate the mitogenesis of endothelial cells and cell migration. VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as a vascular permeability factor.

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Isoform

There are several VEGF-A isoforms produced from alternative mRNA splicing of a single gene, 8-exon VEGFA . These are classified into two groups called by the exon site exon terminal (exon 8): the proximal splice site (denoted VEGF _xxx ) or the distal splice site (VEGF _xxx b). In addition, alternative splicing of exons 6 and 7 alters the affinity of binding of heparin and amino acids (in humans: VEGF ₁₂₁ , VEGF ₁₂₁ b, VEGF ₁₄₅ , VEGF ₁₆₅ , VEGF ₁₆₅ , VEGF ₁₈₉ , rodent orthologists of these proteins containing one less amino acid). This domain has important functional consequences for the VEGF splice variant, since the terminal splice site (exon 8) determines whether pro-angiogenic protein (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed under normal circumstances). network). In addition, the inclusion or exclusion of exons 6 and 7 mediated interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhanced their ability to bind and activate VEGF receptors (VEGFRs). Recently, VEGF-C has been shown to be an important inducer of neurogenesis in the murine subventricular zone, without exerting an angiogenic effect.

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Mechanism

All members of the VEGF family stimulate cellular responses by binding to the tyrosine kinase receptor (VEGFR) on the cell surface, causing them to dimerisation and becoming active through transphosphorylation, albeit to different sites, times and areas. The VEGF receptor has an extracellular portion of 7 domains such as immunoglobulins, 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 seems to mediate almost all known cellular responses to VEGF. The VEGFR-1 function is poorly defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may act as an artificial receptor/feed, confiscating VEGF from the binding of VEGFR-2 (this seems particularly important during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are the ligands for the third receptor (VEGFR-3/Flt4), which mediates lymphangiogenesis. The receptor (VEGFR3) is a major ligand binding site (VEGFC and VEGFD), which mediates continuous ligand action and ligand function in the target cell. The growth factor of the C-vascular endothelial can stimulate lymphangiogenesis (via VEGFR3) and angiogenesis via VEGFR2. R3 vascular endothelial growth factor has been detected in lymphatic endothelial cells in CL of many species, cattle, buffalo and primates.

In addition to binding VEGFR, VEGF binds to a receptor complex consisting of both neuropilin and VEGFR. This receptor complex has increased the activity of VEGF signaling in endothelial cells (blood vessels). Neuropilins (NRP) are pleitropic receptors and therefore other molecules may interfere with signaling from NRP/VEGFR receptors. For example, Class 3 semaphorins compete with VEGF ₁₆₅ for NRP binding and can therefore regulate VEGF-mediated angiogenesis.

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Expression

The production of VEGF-A can be induced in cells that do not receive enough oxygen. When a cell lacks oxygen, it produces HIF, hypoxia-inducible factor, transcription factor. HIF stimulates the release of VEGF-A, among other functions (including erythropoiesis modulation). Circulating VEGF-A then binds to the VEGF Receptor on endothelial cells, triggering Tyrosine Kinase Pathway leading to angiogenesis. Expression of angiopoietin-2 in the absence of VEGF causes endothelial cell death and vascular regression. In contrast, a German study conducted in vivo found that VEGF concentrations actually decreased after a 25% reduction in oxygen intake for 30 min. HIF1 alpha and HIF1 beta are continuously manufactured but HIF1 alpha is highly O ₂ labile, so, under aerobic conditions, it is degraded. When the cell becomes hypoxic, alpha HIF1 settles and the HIF1alpha/beta complex stimulates the release of VEGF.

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Clinical interests

In disease

VEGF-A and associated receptors are rapidly re-regulated after traumatic injury to the central nervous system (CNS). VEGF-A is highly expressed at the acute and sub-acute stage of CNS injury, but protein expression decreases with time. The duration of VEGF-A expression is in accordance with the capacity of endogenous re-vascularization after injury. This will show that VEGF-A/VEGF ₁₆₅ can be used as a target to promote angiogenesis after a traumatic CNS injury. However, there are conflicting scientific reports about the effects of VEGF-A treatment in the CNS injury model.

VEGF-A has been implicated with a poor prognosis in breast cancer. Numerous studies have shown a decrease in overall survival and disease-free survival in tumors that overexpress VEGF. The excessive expression of VEGF-A may be the first step in the process of metastasis, the step involved in the "angiogenic" switch. Although VEGF-A has been correlated with poor survival, the exact mechanism of action in tumor progression remains unclear.

VEGF-A is also released in rheumatoid arthritis in response to TNF-, enhances endothelial permeability and swelling and also stimulates angiogenesis (capillary formation).

VEGF-A is also important in diabetic retinopathy (DR). The microcirculation problem in the diabetic retina may cause retinal ischemia, which results in VEGF-A release, and angiogenic angiogenic balance changes _xxx isoforms above the normally expressed VEGF. _xxx b isoform. VEGF _xxx can lead to the formation of new blood vessels in the retina and elsewhere in the eye, marking changes that can threaten vision.

VEGF-A plays a role in disease pathology from the wet form of age-related macular degeneration (AMD), which is a leading cause of blindness for the elderly from the industrial world. The vascular pathology of AMD has similarities to diabetic retinopathy, although the cause of disease and the distinctive source of neovascularization differ between diseases.

Serum levels of VEGF-D increased significantly in patients with angiosarcoma.

Once released, VEGF-A may generate some responses. It can cause cells to survive, move, or be different. Therefore, VEGF is a potential target for cancer treatment. 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 the efficacy of bevacizumab are unknown.

Current studies show that VEGF is not the only angiogenesis promoter. In particular, FGF2 and HGF are potent angiogenic factors.

Patients with pulmonary emphysema have been found to have decreased VEGF levels in the pulmonary artery.

In the kidney, increased expression of VEGF-A in the glomeruli directly leads to glomerular hypertrophy associated with proteinuria.

VEGF changes can predict early onset of preeclampsia.

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See also

• Protease in angiogenesis
• Withaferin A, the angiogenesis potential inhibitor

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References

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Further reading

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External links

• Endothelial Vascular Growth Factor at National Library of Medicine US Subject of Medical Subject (MeSH)
• Proteopedia Vascular_Endothelial_Growth_Factor - Growth Endothelial Vascular Growth Factor in Interactive 3D

Source of the article : Wikipedia