Vascular endothelial growth factor A

Vascular endothelial growth factor A (VEGF-A) is a is_associated_with::protein that in humans is encoded by the VEGFA is_associated_with::gene.

Function
This gene is a member of the is_associated_with::platelet-derived growth factor (PDGF)/is_associated_with::vascular endothelial growth factor (VEGF) family and encodes a protein that is often found as a disulfide linked homodimer. This protein is a is_associated_with::glycosylated is_associated_with::mitogen that specifically acts on is_associated_with::endothelial cells and has various effects, including mediating increased vascular permeability, inducing is_associated_with::angiogenesis, is_associated_with::vasculogenesis and endothelial cell growth, promoting is_associated_with::cell migration, and inhibiting is_associated_with::apoptosis. Alternatively spliced transcript variants, encoding either freely secreted or cell-associated isoforms, have been characterized.

As its name implies, VEGF-A activity has been studied mostly on cells of the vascular is_associated_with::endothelium, although it does have effects on a number of other cell types (e.g., stimulation is_associated_with::monocyte/is_associated_with::macrophage migration, neurons, cancer cells, kidney epithelial cells ). In vitro, VEGF-A has been shown to stimulate endothelial cell is_associated_with::mitogenesis and is_associated_with::cell migration. VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.

Summary of VEGFA
Vascular endothelial growth factor A (VEGFA) is a dimeric glycoprotein that plays a significant role in neurons and is considered to be the main, dominant inducer to the growth of blood vessels. VEGFA is essential for adults during organ remodeling and diseases that involve blood vessels, for example, in wound healing, tumor angiogenesis, diabetic retinopathy, and age-related macular degeneration. During early vertebrate development, vasculogenesis occurs which means that the endothelial condense into the blood vessels. The differentiation of endothelial cells is dependent upon the expression of VEGFA and if the expression is abolished then it can result in the death of the embryo. VEGFA is produced by a group of three major isoforms as a result of alternative splicing and if any three isoforms are produced (VEGFA120, VEGFA164, and VEGFA188) then this will not result in vessel defects and death of the full VEGFA knockout in mice. VEGFA is essential in the role of neurons because they too need vascular supply and abolishing the expression of VEGFA from neural progenitors will result in defects of the brain vascularization and neuronal apoptosis. Anti-VEGFA therapy can be used to treat patients with undesirable angiogenesis and vascular leakage in cancer and eye diseases but also could result in the inhibition of neurogenesis and neuroprotection. VEGFA could be used to treat patients with neurodegenerative and neuropathic conditions and also increase vascular permeability which will stop the blood-brain barrier and increase inflammatory cell infiltration. References

Usage

 * is_associated_with::Angiogenesis
 * ↑ Migration of is_associated_with::endothelial cells
 * ↑ is_associated_with::mitosis of is_associated_with::endothelial cells
 * ↑ is_associated_with::Matrix metalloproteinase activity
 * ↑ is_associated_with::αvβ3 activity
 * creation of blood vessel lumen
 * creates lumen
 * creates fenestrations
 * is_associated_with::Chemotactic for is_associated_with::macrophages and is_associated_with::granulocytes
 * is_associated_with::Vasodilation (indirectly by NO release)

Also tumour suppression.

Clinical significance
Elevated levels of this protein is linked to is_associated_with::POEMS syndrome, also known as Crow-Fukase syndrome. Mutations in this gene have been associated with proliferative and nonproliferative is_associated_with::diabetic retinopathy.

Treatment of ischemic heart disease
In ischemic is_associated_with::cardiomyopathy, blood flow to the muscle cells of the heart is either partially or completely reduced, leading to cell death and scar tissue formation. Because the muscle cells are replaced with fibrous tissue, the heart loses its ability to contract, compromising heart function. Normally, if blood flow to the heart is compromised, over time, new blood vessels will develop, providing alternative circulation to the affected cells. The viability of the heart following severely restricted blood flow is dependent on the ability of the heart to provide this collateral circulation. Expression of VEGF-A has been found to be induced by myocardial ischemia and a higher level of expression of VEGF-A has been associated with better collateral circulation development during ischemia.

VEGF-A activation
When cells are deprived of oxygen, they increase their production of VEGF-A5. VEGF-A mediates the growth of new blood vessels from pre-existing vessels (angiogenesis) by binding to the cell surface receptors VEGFr1 and VEGFr2, two tyrosine kinases located in endothelial cells of the cardiovascular system. These two receptors act through different pathways to contribute to endothelial cell proliferation and migration, and formation of tubular structures.

VEGFr2
The binding of VEGF-A to VEGFr2 causes two VEGFr2 molecules to combine to form a dimer. Following this dimerization, through the action of the receptor itself, a phosphate group is added to certain tyrosines within the molecule in a process called auto-is_associated_with::phosphorylation. The autophosphorylation of these amino acids allows for signalling molecules within to the cell to bind to the receptor and become activated. These signalling molecules include VEGF-receptor activated protein (VRAP), PLC- γ and Nck.

Each of these is important in the signalling required for angiogenesis. VRAP (also known as T-cell specific adaptor) and Nck signalling are important in reorganization of the structural components of the cell, allowing for cells to move around to areas where they are needed. PLC- γ is vital to the proliferative effects of VEGF-A signalling. Activation of the phospholipase PLC- γ results in an increase in calcium levels in the cell, leading to the activation of is_associated_with::protein kinase C (PKC). PKC phosphorylates the is_associated_with::mitogen-activated protein kinase (MAPK) ERK which then moves to the nucleus of the cell and takes part in nuclear signalling. Once in the nucleus, ERK activates various transcription factors which initiate expression of genes involved in cellular proliferation. Activation of a different MAPK (p38 MAPK) by VEGFr2 is important in the transcription of genes associated with cellular migration.

VEGFr
The is_associated_with::tyrosine kinase activity of VEGFr1 is less efficient than that of VEGFr218 and its activation alone is insufficient to bring about the proliferative effects of VEGF-A. The major role of VEGFr1 is to recruit the cells responsible in blood cell development.

Current research
It has been shown that injection of VEGF-A in dogs following severely restricted blood flow to the heart caused an increase in collateral blood vessel formation compared to the dogs who did not receive the VEGF-A treatment. It was also shown in dogs that delivery of VEGF-A to areas of the heart with little or no blood flow enhanced collateral blood vessel formation and increased the viability of the cells in that area. In gene therapy, DNA which encodes the gene of interest is integrated into a vector along with elements that are able to promote the gene’s expression. The vector is then injected either into muscle cells of the heart or the blood vessels supplying the heart. The natural machinery of the cell is then used to express these genes. Currently, human clinical trials are being conducted to study the effectiveness of gene therapy with VEGF-A in restoring blood flow and function to areas of the heart that have severely restricted blood flow. So far, this type of therapy has proven both safe and beneficial.

Interactions
Vascular endothelial growth factor A has been shown to interact with:
 * is_associated_with::ADAMTS1,
 * is_associated_with::CTGF, and
 * NRP1,