Vascular endothelial growth factor A
Encyclopedia
Vascular endothelial growth factor A (VEGF-A) is a protein
that in humans is encoded by the VEGFA gene
.
(PDGF)/vascular endothelial growth factor
(VEGF) family and encodes a protein that is often found as a disulfide linked homodimer. This protein is a glycosylated mitogen
that specifically acts on endothelial cells and has various effects, including mediating increased vascular permeability, inducing angiogenesis
, vasculogenesis
and endothelial cell growth, promoting cell migration
, and inhibiting 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 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.
Also tumour suppression.
, also known as Crow-Fukase syndrome. Mutations in this gene have been associated with proliferative and nonproliferative diabetic retinopathy
.
, 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.
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.
. 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.
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.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the VEGFA gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
This gene is a member of the platelet-derived growth factorPlatelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
(PDGF)/vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) family and encodes a protein that is often found as a disulfide linked homodimer. This protein is a glycosylated mitogen
Mitogen
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....
that specifically acts on endothelial cells and has various effects, including mediating increased vascular permeability, inducing angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, vasculogenesis
Vasculogenesis
Vasculogenesis is the process of blood vessel formation occurring by a de novo production of endothelial cells.-Process:Though similar to angiogenesis, the two are different in one aspect: The term angiogenesis denotes the formation of new blood vessels from pre-existing ones, whereas...
and endothelial cell growth, promoting cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, and inhibiting apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Alternatively spliced
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
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 endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, although it does have effects on a number of other cell types (e.g., stimulation monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
/macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
migration, neurons, cancer cells, kidney epithelial cells ). In vitro, VEGF-A has been shown to stimulate endothelial cell mitogenesis and cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
. VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.
Usage
- AngiogenesisAngiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
- ↑ MigrationCell migrationCell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
of endothelial cells - ↑ mitosisMitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
of endothelial cells - ↑ Matrix metalloproteinaseMatrix metalloproteinaseMatrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
activity - ↑ αvβ3 activity
- creation of blood vessel lumenLumen (anatomy)A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
- creates lumenLumen (anatomy)A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
- creates fenestrations
- ↑ Migration
- Chemotactic for macrophages and granulocytes
- VasodilationVasodilationVasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
(indirectly by NONitric oxideNitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
release)
Also tumour suppression.
Clinical significance
Elevated levels of this protein is linked to POEMS syndromePOEMS syndrome
POEMS syndrome is a rare medical syndrome. It is defined as the combination of a plasma-cell proliferative disorder , polyneuropathy, and effects on many other organ systems. It begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women...
, also known as Crow-Fukase syndrome. Mutations in this gene have been associated with proliferative and nonproliferative diabetic retinopathy
Diabetic retinopathy
Diabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
.
Treatment of ischemic heart disease
In ischemic cardiomyopathyCardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
, 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 VEGFr1FLT1
Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the FLT1 gene.-Interactions:FLT1 has been shown to interact with PLCG1 and Vascular endothelial growth factor B.-Further reading:...
and VEGFr2
Kinase insert domain receptor
Kinase insert domain receptor also known as vascular endothelial growth factor receptor 2 is a VEGF receptor. KDR is the human gene encoding it. KDR has also been designated as CD309...
, 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-phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. 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
SH2D2A
SH2 domain-containing protein 2A is a protein that in humans is encoded by the SH2D2A gene.-Further reading:...
), PLC- γ
PLCG1
Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
and Nck
NCK1
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.-Interactions:NCK1 has been shown to interact with DNM1, EIF2B2, KHDRBS1, Lymphocyte cytosolic protein 2, EPH receptor B1, SOCS7, MINK1, MAP4K1, MAP4K4, Abl gene, WIPF1, RRAS, Wiskott-Aldrich syndrome protein,...
.
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
PLCG1
Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
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
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC). PKC phosphorylates the mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
(MAPK) ERK
MAPK1
Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...
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
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
) by VEGFr2 is important in the transcription of genes associated with cellular migration.
VEGFr
The tyrosine kinaseTyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- ADAMTS1ADAMTS1A disintegrin and metalloproteinase with thrombospondin motifs 1 is an enzyme that in humans is encoded by the ADAMTS1 gene.-Interactions:ADAMTS1 has been shown to interact with Vascular endothelial growth factor A.-External Links:...
, - CTGFCTGFCTGF is a cysteine-rich, matrix-associated, heparin-binding protein. In vitro, CTGF mirrors some of the effects of TGF beta on skin fibroblasts, such as stimulation of extracellular matrix production, chemotaxis, proliferation and integrin expression...
, and - NRP1Neuropilin 1Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene.. This is one of two human neuropilins.-Interactions:Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A.-Further reading:...
,
See also
- Vascular endothelial growth factorVascular endothelial growth factorVascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
- BevacizumabBevacizumabBevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
(or Avastin) anti VEGF-A human antibody drug.