Vascular endothelial growth factor

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity has been mostly studied 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 has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.

Classification

Schematic representation of The different isoforms of human VEGF

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 familes 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: VEGF₁₂₁, VEGF₁₂₁b, VEGF₁₄₅, VEGF₁₆₅, VEGF₁₆₅b, VEGF₁₈₉, VEGF₂₀₆; 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).

Function

Crystal structure of Vammin, a VEGF-F from a snake venom

The VEGF splice variants are released from cells as glycosylated disulfide-bonded dimers. Structurally VEGF belongs to the PDGF family of cystine-knot growth factors. Subsequently, several closely-related proteins were discovered (Placenta growth factor (PlGF), VEGF-B, VEGF-C and VEGF-D) which together comprise the VEGF sub-family of growth factors. VEGF is sometimes referred to as VEGF-A to differentiate it from these related growth factors. A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F).

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 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 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 (Disease-free survival) in those tumors overexpressing VEGF. The overexpression of VEGF_xxx may be an early step in the process of metastasis, 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 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 [2] 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 is associated with proteinuria.

Anti-VEGF therapies

Anti-VEGF therapies [3] 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 07) at ASCO.

External links

• ResearchVEGF.com
• Vascular+Endothelial+Growth+Factors at the US National Library of Medicine Medical Subject Headings (MeSH)
• VEGF antibody

Further reading

• Ferrara N, Gerber HP (2002). "The role of vascular endothelial growth factor in angiogenesis". Acta Haematol. 106 (4): 148–56. PMID 11815711.
• Orpana A, Salven P (2003). "Angiogenic and lymphangiogenic molecules in hematological malignancies". Leuk. Lymphoma. 43 (2): 219–24. PMID 11999550.
• Afuwape AO, Kiriakidis S, Paleolog EM (2003). "The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis". Histol. Histopathol. 17 (3): 961–72. PMID 12168808.CS1 maint: Multiple names: authors list (link)
• de Bont ES, Neefjes VM, Rosati S; et al. (2003). "New vessel formation and aberrant VEGF/VEGFR signaling in acute leukemia: does it matter?". Leuk. Lymphoma. 43 (10): 1901–9. PMID 12481883.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Ria R, Roccaro AM, Merchionne F; et al. (2003). "Vascular endothelial growth factor and its receptors in multiple myeloma". Leukemia. 17 (10): 1961–6. doi:10.1038/sj.leu.2403076. PMID 14513045.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Caldwell RB, Bartoli M, Behzadian MA; et al. (2004). "Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives". Diabetes Metab. Res. Rev. 19 (6): 442–55. doi:10.1002/dmrr.415. PMID 14648803.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Patan S (2004). "Vasculogenesis and angiogenesis". Cancer Treat. Res. 117: 3–32. PMID 15015550.
• Machein MR, Plate KH (2004). "Role of VEGF in developmental angiogenesis and in tumor angiogenesis in the brain". Cancer Treat. Res. 117: 191–218. PMID 15015562.
• Eremina V, Quaggin SE (2004). "The role of VEGF-A in glomerular development and function". Curr. Opin. Nephrol. Hypertens. 13 (1): 9–15. PMID 15090854.
• Storkebaum E, Lambrechts D, Carmeliet P (2004). "VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection". Bioessays. 26 (9): 943–54. doi:10.1002/bies.20092. PMID 15351965.CS1 maint: Multiple names: authors list (link)
• Ribatti D (2005). "The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review". Br. J. Haematol. 128 (3): 303–9. doi:10.1111/j.1365-2141.2004.05291.x. PMID 15667531.
• Loureiro RM, D'Amore PA (2005). "Transcriptional regulation of vascular endothelial growth factor in cancer". Cytokine Growth Factor Rev. 16 (1): 77–89. doi:10.1016/j.cytogfr.2005.01.005. PMID 15733833.
• Rini BI (2005). "VEGF-targeted therapy in metastatic renal cell carcinoma". Oncologist. 10 (3): 191–7. doi:10.1634/theoncologist.10-3-191. PMID 15793222.
• Herbst RS, Onn A, Sandler A (2005). "Angiogenesis and lung cancer: prognostic and therapeutic implications". J. Clin. Oncol. 23 (14): 3243–56. doi:10.1200/JCO.2005.18.853. PMID 15886312.CS1 maint: Multiple names: authors list (link)
• Pufe T, Kurz B, Petersen W; et al. (2006). "The influence of biomechanical parameters on the expression of VEGF and endostatin in the bone and joint system". Ann. Anat. 187 (5–6): 461–72. PMID 16320826.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Tong JP, Yao YF (2006). "Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions". Clin. Biochem. 39 (3): 267–76. doi:10.1016/j.clinbiochem.2005.11.013. PMID 16409998.
• Lambrechts D, Carmeliet P (2007). "VEGF at the neurovascular interface: therapeutic implications for motor neuron disease". Biochim. Biophys. Acta. 1762 (11–12): 1109–21. doi:10.1016/j.bbadis.2006.04.005. PMID 16784838.
• Matsumoto T, Mugishima H (2006). "Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis". J. Atheroscler. Thromb. 13 (3): 130–5. PMID 16835467.
• Bogaert E, Van Damme P, Van Den Bosch L, Robberecht W (2006). "Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases". Muscle Nerve. 34 (4): 391–405. doi:10.1002/mus.20609. PMID 16856151.CS1 maint: Multiple names: authors list (link)
• Mercurio AM, Lipscomb EA, Bachelder RE (2006). "Non-angiogenic functions of VEGF in breast cancer". Journal of mammary gland biology and neoplasia. 10 (4): 283–90. doi:10.1007/s10911-006-9001-9. PMID 16924371.CS1 maint: Multiple names: authors list (link)
• Makinde T, Murphy RF, Agrawal DK (2007). "Immunomodulatory role of vascular endothelial growth factor and angiopoietin-1 in airway remodeling". Curr. Mol. Med. 6 (8): 831–41. PMID 17168735.CS1 maint: Multiple names: authors list (link)
• Rini BI, Rathmell WK (2007). "Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma". Clin. Cancer Res. 13 (2 Pt 2): 741s–746s. doi:10.1158/1078-0432.CCR-06-2110. PMID 17255303.