VEGF
||image_reduire{0,60}|inserer_attribut{alt,VEGF and DLL4 signaling})Definition: Vascular endothelial growth factor (VEGF) is a regulator of developmental, hypoxia-induced, and tumor-induced angiogenesis.
Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions.
The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR1 and VEGFR2, which differ considerably in signaling properties.
Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies.
VEGFRs
Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively.
VEGF and DLL4 signaling
DLL4 signalling acts downstream of VEGF signalling to prevent excessive angiogenesis and to trigger terminal differentiation of newly forming vessels.
VEGF-A is a prime regulator of vessel elongation, acting through the activation of EC proliferation and EC survival. Activation of VEGF-R2 by VEGF-A occurs early during sprouting angiogenesis.
Concomitantly, VEGF-A up-regulates Notch signalling pathway locally through the activation of Dll4 expression. Dll4 in turn signals through Notch1 and Notch4 to block excessive branching by preventing the tip cell phenotype.
Finally, Dll4 regulates vessel maturation through inhibition of EC proliferation, recruitment of mural cells and potentially through arterial–venous differentiation.
Dll4-dependent activation of Notch signalling also acts through a negative feedback mechanism to block VEGF signalling through induction of VEGF-R1 and repression of VEGF-R2.
Pathology
Variants in susceptibility to
- diabetic retinopathy in type 2 diabetes
- atherosclerosis
- Alzheimer disease
- amyotrophic lateral sclerosis (ALS)
Cancer
- The possible role of vascular endothelial growth factor (VEGF) in cancer has received much attention because VEGF increases vascular permeability and enhances angiogenesis.
- Overexpression of VEGF has been reported in ovarian carcinomas.
Asthma
- VEGF has been reported to contribute to non-specific airway hyper-responsiveness, have chemotactic effects on eosinophils, and enhance airway smooth muscle cell proliferation. Furthermore, Th2 cells have receptors for VEGF, and Th2-associated cytokines increase VEGF production. There are reports that elevated levels of VEGF correlates with the severity of asthma. (#17168735#)
ALS
- Deletion of the hypoxia response element (HRE) in the murine VEGF promoter resulted in ALS-like disease in mice.
- VEGF is widely expressed throughout the central nervous system (CNS) and can function as a neurotrophic factor for multiple neuronal cell types, including motor neurons.
- Screening of ALS patient DNAs in promoter regions of the VEGF gene, including the HRE and regions known to correlate with downregulation of VEGF synthesis, found no link between HRE variants and disease.
- VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.
- Two haplotypes in other regions of the promoter showed an increased risk of developing ALS in a Belgian, Swedish, and a British/Birmingham population, but this has not been confirmed in other populations.
References
Makinde T, Murphy RF, Agrawal DK. Immunomodulatory role of vascular endothelial growth factor and angiopoietin-1 in airway remodeling. Curr Mol Med. 2006 Dec;6(8):831-41. PMID: #17168735#
Duda DG, Batchelor TT, Willett CG, Jain RK. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med. 2007 Jun;13(6):223-30. PMID: #17462954#
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006 May;7(5):359-71. PMID: #16633338#
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669-76. PMID: #12778165#
Lambrechts D, Storkebaum E, Carmeliet P. VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS? Trends Mol Med. 2004 Jun;10(6):275-82. PMID: #15177192#
Greenberg DA, Jin K. VEGF and ALS: the luckiest growth factor? Trends Mol Med. 2004 Jan;10(1):1-3. PMID: #14720577#
Rabbany SY, Heissig B, Hattori K, Rafii S. Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization. Trends Mol Med. 2003 Mar;9(3):109-17. PMID: #12657432#
Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002 Oct;2(10):795-803. PMID: #12360282#
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669-76. PMID: #12778165#