Vascular endothelial growth factor (
VEGF) 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.
Serum concentration of VEGF is high in Bronchial Asthma and low in Diabetes Mellitus
VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (
collateral circulationCollateral circulation is when an area of tissue or an organ has a number of different pathways for blood to reach it. This is often as a result of anastamoses - branches formed between adjacent blood vessels....
) to bypass blocked vessels.
When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the
retinaThe vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
of the eye and other parts of the body. Drugs such as
bevacizumabBevacizumab 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....
can inhibit VEGF and control or slow those diseases.
VEGF is a sub-family of growth factors, to be specific, the
platelet-derived growth factorIn 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...
family of cystine-knot growth factors. They are important signaling
proteinProteins 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...
s involved in both
vasculogenesisVasculogenesis 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...
(the
de novoIn general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
formation of the embryonic
circulatory systemThe circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
) and
angiogenesisAngiogenesis 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...
(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).
Comparison
| Type | Function |
| VEGF-A |
- 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...
- ↑ 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...
of endothelial cells
- ↑ mitosis
Mitosis 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
- ↑ Methane monooxygenase
Methane monooxygenase, or MMO, is an enzyme capable of oxidizing the C-H bond in methane as well as other alkanes. Methane monooxygenase belongs to the class of oxidoreductase enzymes ....
activity
- ↑ αvβ3 activity
- creation of blood vessel lumen
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
- creates fenestrations
- Chemotactic for macrophages and granulocytes
- Vasodilation
Vasodilation 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 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) |
| VEGF-B |
Embryonic angiogenesis (myocardial tissue, specifically) |
| VEGF-C |
Lymphangiogenesis Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels, in a method believed to be similar to blood vessel development or angiogenesis....
|
| 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. |
Activity of
VEGF-A, as its name implies, has been studied mostly on cells of the vascular
endotheliumThe 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
monocyteMonocytes 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...
/
macrophageMacrophages 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 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...
. 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
splicingIn molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
of mRNA from a single, 8-
exonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
,
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
heparinHeparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
-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 sulfateHeparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
proteoglycans (HSPGs) and
neuropilinNeuropilin is a protein receptor active in neurons.There are two forms of Neuropilins, NRP-1 and NRP-2. They are transmembrane glycoproteins, and predominantly co-receptors for another class of proteins known as semaphorins...
co-receptors on the cell surface, enhancing their ability to bind and activate the
VEGF receptorsVEGF receptors are receptors for vascular endothelial growth factor . There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound or soluble , depending on alternative splicing.-VEGF:...
(VEGFRs).
Mechanism
All members of the VEGF family stimulate cellular responses by binding to
tyrosine kinaseA 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....
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 is 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
lymphangiogenesisLymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels, in a method believed to be similar to blood vessel development or angiogenesis....
.
Production
VEGF
xxx production can be induced in cells that are not receiving enough
oxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
. 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 KinaseA 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....
Pathway leading to angiogenesis.
HIF1 alpha and HIF1 beta are constantly being produced but HIF1 alpha is highly O
2 labile, so, in aerobic conditions, it is degraded. When the cell becomes hypoxic, HIF1 alpha persists and the HIF1alpha/beta complex stimulates VEGF release.
VEGF in disease
VEGF
xxx has been implicated with poor prognosis in
breast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGF
xxx may be an early step in the process of
metastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
, a step that is 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 arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
in response to TNF-α, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).
VEGF
xxx is also important in
diabetic retinopathyDiabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
(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 that 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
angiosarcomaHemangiosarcoma is a rare, rapidly growing, highly invasive variety of cancer. It is a sarcoma arising from the lining of blood vessels; that is, blood-filled channels and spaces are commonly observed microscopically...
.
Once released, VEGF
xxx may elicit several responses. It may cause a
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of
cancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. The first anti-VEGF drug, a monoclonal antibody named
bevacizumabBevacizumab 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....
, was approved in 2004. Approximately 10-15% of patients benefit from bevacizumab therapy; however, 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 are potent angiogenic factors.
Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.
In the
kidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, increased expression of VEGF
xxx in
glomeruliA glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...
directly causes the glomerular hypertrophy that is associated with proteinuria.
Anti-VEGF therapies
Anti-VEGF therapies are important in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as
bevacizumabBevacizumab 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....
(Avastin), antibody derivatives such as
ranibizumabRanibizumab is a monoclonal antibody fragment derived from the same parent mouse antibody as bevacizumab . It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A...
(Lucentis), or orally-available small molecules that inhibit the
tyrosine kinaseA 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....
s stimulated by VEGF:
lapatinibLapatinib , used in the form of lapatinib ditosylate, is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. It is used in combination therapy for HER2-positive breast cancer...
(Tykerb),
sunitinibSunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...
(Sutent),
sorafenibSorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
(Nexavar),
axitinibAxitinib is a small molecule tyrosine kinase inhibitor under development by Pfizer. It inhibits multiple targets, including VEGFR-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor , and cKIT...
, and
pazopanibPazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib may also be...
. (Some of these therapies target VEGF receptors rather than the VEGFs.) THC and Cannabidiol both inhibit VEGF and slow Glioma growth.
Both antibody-based compounds are commercialized. The first three orally available compounds are commercialized, as well. The latter two (
axitinibAxitinib is a small molecule tyrosine kinase inhibitor under development by Pfizer. It inhibits multiple targets, including VEGFR-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor , and cKIT...
and
pazopanibPazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib may also be...
) are in clinical trials, the results of which were presented (June 7) at the
American Society of Clinical OncologyThe American Society of Clinical Oncology is the world's leading professional organization representing physicians of all oncology subspecialties who care for people with cancer. Founded in 1964 by Drs...
meeting.
Bergers and Hanahan concluded in 2008 that anti-VEGF drugs can show therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. But, "the benefits are at best transitory and are followed by a restoration of tumour growth and progression."
AZ2171 (
CediranibCediranib , also known as AZD2171, is a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases....
), a multi-targeted tyrosine kinase inhibitor has been shown to have anti-edema effects by reducing the permeability and aiding in vascular normalization.
Pre-clinical
VEGF is also inhibited by thiazolidinediones (used for
diabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
type 2 and related disease), and this effect on
granulosa cellA granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.-Anatomy and function:...
s gives the potential of thiazolidinediones to be used in
ovarian hyperstimulation syndromeOvarian hyperstimulation syndrome is a complication from some forms of fertility medication. Most cases are mild, but a small proportion are severe.-Causative medications:...
.
Neovascular age-related macular degeneration
RanibizumabRanibizumab is a monoclonal antibody fragment derived from the same parent mouse antibody as bevacizumab . It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A...
, a monoclonal antibody fragment (Fab) derived from
bevacizumabBevacizumab 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....
, has been developed by Genetech for intraocular use. In 2004, FDA approved the drug for to treat neovascular age-related macular degeneration (wet AMD). The drug has undergone extensive clinical trials.
In the October 2006 issue of the New England Journal of Medicine (NEJM), Rosenfield, et al. reported that monthly intravitreal injection of ranibizumab led to significant increase in the level of mean visual acuity compared to that of sham injection. It was concluded from the two year, phase III study that ranibizumab is very effective in the treatment of minimally classic (MC) or occult wet AMD (age-related
macular degenerationAge-related macular degeneration is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults...
) with low rates of ocular adverse effects.
Another study published in the January 2009 issue of Ophthalmology provides the evidence for the efficacy of ranibizumab. Brown, et al. reported that monthly intravitreal injection of ranibizumab led to significant increase in the level of mean visual acuity compared to that of
photodynamic therapyPhotodynamic therapy is used clinically to treat a wide range of medical conditions, including malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic...
with
verteporfinVerteporfin , a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration...
. It was concluded from the two year, phase III study that ranibizumab was superior to photodynamic therapy with verteporfin in the treatment of predominantly classic (PC) Wet AMD with low rates of ocular adverse effects.
Although the efficacy of ranibizumab is well supported by extensive clinical trials, the cost effectiveness of the drug is questioned. Since the drug merely stabilizes patient conditions, ranibizumab must be administered monthly. At a cost of $2,000.00 per injection, the cost to treat wet AMD patients in the United States is greater than $10.00 billion per year. Due to high cost, many ophthalmologists have turned to bevacizumab as the alternative intravitreal agent in the treatment of wet AMD. The drug costs $15.00 to 50.00 in the United States.
In 2007, Raftery, et al. reported in the British Journal of Ophthalmology that, unless ranibizumab is 2.5 times more effective the bevacizumab, ranibizumab is not cost effective. It was concluded that the price of ranibizumab would have to be drastically reduced for the drug to be cost effective.
Off-label use of intravitreal bevacizumab has become a widespread treatment for neovascular age-related macular degeneration. Although the drug is not FDA approved for oncologic uses, some studies suggest that bevacizumab is effective in increasing visual acuity with low rates of ocular adverse effects. However, due to small sample size and lack of randomized control trial, the result is not conclusive.
In October 2006, the National Eye Institute (NEI) of the National Institutes of Health (NIH) announced that it would fund a comparative study trial of ranibizumab and bevacizumab to assess the relative efficacy and ocular adversity in treating wet AMD. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), will enroll about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to different treatment groups.
Further reading