Everything about Vascular Endothelial Growth Factor totally explained
Vascular endothelial growth factor (
VEGF) a sub-family of
growth factors, more specifically of
platelet-derived growth factor family of cystine-knot growth factors. They are important signaling
proteins involved in both
vasculogenesis (the
de novo formation of the embryonic
circulatory system) and
angiogenesis (the growth of blood vessels from pre-existing vasculature).
Classification
The most important member is
VEGF-A. Other members are Placenta growth factor (
PlGF),
VEGF-B,
VEGF-C and
VEGF-D. The latter ones were discovered later than VEGF-A, and before their discovery VEGF-A was called just VEGF.
A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F).
| Type |
Function |
| VEGF-A | |
| VEGF-B | Embryonic angiogenesis
|
| VEGF-C | Lymphangiogenesis
|
| VEGF-D | Needed for the development of lymphatic vasculature surrounding lung bronchioles
|
| PlGF | Important for Vasculogenesis, Also needed for angiogenesis during ischemia, inflammation, wound healing, and cancer.
|
As its name implies,
VEGF-A activity has been mostly studied on cells of the vascular
endothelium, although it does have effects on a number of other cell types (for example 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.
Alternative classification
The broad term 'VEGF' covers a number of proteins from two families, that result from alternate
splicing of
mRNA from a single, 8
exon,
VEGF gene. The two different families are referred to according to their terminal exon (exon 8) splice site - the proximal splice site (denoted VEGF
xxx) or distal splice site (VEGF
xxxb). In addition, alternate splicing of exon 6 and 7 alters their heparin binding affinity, and amino acid number (in humans: VEGF
121, VEGF
121b, VEGF
145, VEGF
165, VEGF
165b, VEGF
189, VEGF
206; the rodent orthologs of these proteins contain one fewer amino acid). These domains have important functional consequences for the VEGF splice variants as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). In addition inclusion or exclusion of exons 6 and 7 mediate interactions with
heparan sulfate proteoglycans (HSPGs) and
neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the VEGF signaling receptors (VEGFRs).
Mechanism
All members of the VEGF family stimulate cellular responses by binding to
tyrosine kinase receptors (the
VEGFRs) on the cell surface, causing them to dimerize and become activated through
transphosphorylation, although to different sites, times and extents. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, 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 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it's thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor (VEGFR-3), which mediates
lymphangiogenesis.
Production
VEGF
xxx production can be induced in cells that are not receiving enough
oxygen. When a cell is deficient in oxygen, it produces HIF,
Hypoxia Inducible Factor, a transcription factor. HIF stimulates the release of VEGF
xxx, among other functions (including modulation of erythropoeisis). Circulating VEGF
xxx then binds to VEGF Receptors on endothelial cells, triggering a
Tyrosine Kinase Pathway leading to angiogenesis.
Clinical significance
VEGF
xxx has been implicated with poor prognosis in
breast cancer. Numerous studies show a decreased
OS and
DFS in those tumors overexpressing VEGF. The overexpression of VEGF
xxx may be an early step in the process of
metastasis, a step that's involved in the "angiogenic" switch. Although VEGF
xxx has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.
VEGF
xxx is also released in
rheumatoid arthritis in response to TNF-α, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).
VEGF
xxx is also important in
diabetic retinopathy (DR). The microcirculatory problems in the retina of people with
diabetes can cause retinal ischaemia, which results in the release of VEGF
xxx, and a switch in the balance of pro-angiogenic VEGF
xxx isoforms over the normally expressed VEGF
xxxb isoforms. VEGF
xxx may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight.
VEGF
xxx plays a role in the disease pathology of the wet form
age-related macular degeneration (AMD), which is the leading cause of blindness for the elderly of the industrialized world. The vascular pathology of AMD shares certain similarities with diabetic retinopathy, although the cause of disease and the typical source of neovascularization differes between the two diseases.
VEGF-D serum levels are significantly elevated in patients with
angiosarcoma (PMID 14746640)
Once released, VEGF
xxx may elicit several responses. It may cause a
cell to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of
cancer. The first anti-VEGF drug, a
monoclonal antibody named
bevacizumab, was approved in 2004. Approximately 10-15% of patients benefit from bevacizumab therapy, although biomarkers for bevacizumab efficacy are not yet known.
Current studies show that VEGFs are not the only promoters of angiogenesis. In particular
FGF2 and HGF
(External Link
) are potent angiogenic factors.
Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.
In the
kidney increased expression of VEGF
xxx in
glomeruli directly causes the glomerular hypertrophy that's associated with proteinuria.
Anti-VEGF therapies
Anti-VEGF therapies
(External Link) are important in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as
bevacizumab (Avastin), antibody derivatives such as
ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF:
sunitinib (Sutent),
sorafenib (Nexavar), axitinib, and pazopanib. Both antibody-based compounds are commercialized. The first two orally available compounds are commercialized, as well. The latter two are in clinical trials, the results of which were presented (
June 7) at ASCO.
Further Information
Get more info on 'Vascular Endothelial Growth Factor'.
|
External Link Exchanges
Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:
<a href="http://vascular_endothelial_growth_factor.totallyexplained.com">Vascular endothelial growth factor Totally Explained</a>
Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
