Vascular endothelial growth factor: Wikis

  

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Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate.

VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) 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 retina of the eye and other parts of the body. Drugs such as bevacizumab can inhibit VEGF and control or slow those diseases.

VEGF is a sub-family of growth factors, specifically the 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).

Contents

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.

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

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
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.

Activity of VEGF-A, as its name implies, 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.

Alternative 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 families are referred to according to their terminal exon (exon 8) splice site - the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb). 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 receptors (VEGFRs).

Types of VEGF and their VEGF receptors.[1]

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 [2]. 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

VEGFxxx 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 VEGFxxx, among other functions (including modulation of erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to angiogenesis.

HIF1 alpha and HIF1 beta are constantly being produced but HIF1 alpha is highly O2 labile, so, in aerobic conditions, it is degraded. When the cell becomes hypoxic, HIF1 alpha persists and the HIF1alpha/beta complex stimulates VEGF release.

Clinical significance

VEGFxxx has been implicated with poor prognosis in breast cancer. Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that is involved in the "angiogenic" switch. Although VEGFxxx has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.

VEGFxxx is also released in rheumatoid arthritis in response to TNF-α, increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).

VEGFxxx 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 VEGFxxx, and a switch in the balance of pro-angiogenic VEGFxxx isoforms over the normally expressed VEGFxxxb isoforms. VEGFxxx may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight.

VEGFxxx 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.[3]

Once released, VEGFxxx 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; 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 kidney, increased expression of VEGFxxx in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria.[4]

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 bevacizumab (Avastin), antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: lapatinib (Tykerb), sunitinib (Sutent), sorafenib (Nexavar), axitinib, and pazopanib.

Both antibody-based compounds are commercialized. The first three orally available compounds are commercialized, as well. The latter two are in clinical trials, the results of which were presented (June 7) at the American Society of Clinical Oncology 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." [5]

AZ2171, a multi-targeted tyrosine kinase inhibitor has been shown to have antiedema effects by reducing the permeability and aiding in vascular normalization.

References

  1. ^ cancerpublications.com.
  2. ^ Holmes K, Roberts OL, Thomas AM, Cross MJ. (Oct 2007). "Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition.". Cell Signal. 19 (10): 2003–2012. PMID 17658244.  
  3. ^ Amo Y, Masuzawa M, Hamada Y, Katsuoka K (January 2004). "Serum concentrations of vascular endothelial growth factor-D in angiosarcoma patients". Br. J. Dermatol. 150 (1): 160–1. doi:10.1111/j.1365-2133.2004.05751.x. PMID 14746640. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-0963&date=2004&volume=150&issue=1&spage=160.  
  4. ^ Liu E, Morimoto M, Kitajima S, et al. (July 2007). "Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions". J. Am. Soc. Nephrol. 18 (7): 2094–104. doi:10.1681/ASN.2006010075. PMID 17554151.  
  5. ^ Bergers G, Hanahan D (August 2008). "Modes of resistance to anti-angiogenic therapy". Nat. Rev. Cancer 8 (8): 592–603. doi:10.1038/nrc2442. PMID 18650835. http://www.nature.com/nrc/journal/v8/n8/abs/nrc2442.html.  

External links

Further reading

  • Ferrara N, Gerber HP (2002). "The role of vascular endothelial growth factor in angiogenesis". Acta Haematol. 106 (4): 148–56. doi:10.1159/000046610. PMID 11815711.  
  • Orpana A, Salven P (2003). "Angiogenic and lymphangiogenic molecules in hematological malignancies". Leuk. Lymphoma 43 (2): 219–24. doi:10.1080/10428190290005964. 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.  
  • 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. doi:10.1080/1042819021000015844. PMID 12481883.  
  • 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.  
  • 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.  
  • 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. doi:10.1097/00041552-200401000-00002. 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.  
  • 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.  
  • 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. doi:10.1016/j.aanat.2005.06.008. PMID 16320826.  
  • 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.  
  • 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.  
  • 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. doi:10.2174/156652406779010795. PMID 17168735.  
  • 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.  
  • Rodgers LS, Lalani S, Hardy KM, Xiang X, Broka D, Antin PB, Camenisch TD. (2006). "Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation.". Circ Res. 99 (6): 583–9. doi:10.1161/01.RES.0000242561.95978.43. PMID 16931798.  







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