Elevated levels of this protein is linked to
POEMS syndrome, also known as Crow-Fukase syndrome. Mutations in this gene have been associated with proliferative and nonproliferative
diabetic retinopathy.
Treatment of ischemic heart disease In ischemic
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-A. 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-
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
protein kinase C (PKC). PKC phosphorylates the
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.
VEGFR1 The
tyrosine kinase activity of VEGFR1 is less efficient than that of VEGFR2 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. 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==