angiogenesis

Angiogenesis is a multistep process by which new vessels arise from pre-existing vasculature.

During the angiogenic switch, which is triggered by an increase in pro-angiogenic and/or a decrease in angiostatic molecules, endothelial cells (ECs) become activated and degrade the surrounding basal lamina. This enables activated cells to sprout towards the angiogenic stimuli. The direction of migration of the new sprouts is dictated by the so-called leading ‘tip cells’ that harbour long filopodia extensions that screen the surrounding environment for growth factors, such as VEGF.

Vessel elongation requires proliferation within the stalk cells that become polarized subsequently to generate the vessel lumina.

Stabilization and maturation of nascent vessels require the generation of a new basement membrane and the recruitment of mural cells, such as pericytes.

Finally, through fusion to an existing vessel (a process named anastomosis), angiogenesis is completed and continuous blood flow is initiated. Although angiogenesis occurs mainly during embryonic development, it is also observed in adults in whom both physiological (e.g. wound healing, menstruation cycle) and pathological (e.g. age-related macular degeneration, psoriasis and solid tumour growth) neovascularization occurs.

Therapeutics

Thus, several therapeutic approaches targeting several of the steps described have been generated to treat pathologies associated with deregulated angiogenesis.

Current anti-angiogenic therapy targets mainly the signalling between VEGF-A and VEGF-R2. These inhibitors are effective in the treatment of several different cancers. However, the increasing number of tumours not responding or becoming insensitive to these treatments has forced the development of alternative approaches.

Recently, exciting data from several studies have demonstrated that the DLL4–NOTCH1 signalling pathway prevents excessive angiogenesis through the inhibition of branching and by triggering vessel maturation.

More interestingly, blocking this signalling pathway in vivo delays tumour growth significantly by triggering excessive but nonfunctional angiogenesis, thus constituting a new class of anticancer agents.

See also

 angiogenesis inhibitors
 embryonal angiogenesis
 inflammatory angiogenesis
 tumoral angiogenesis
 lymphangiogenesis
 angiogenesis-related genes

Videos

 VEGF and VEGFRs

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 tumoral angiogenesis

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References

 Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis. Buysschaert I, Schmidt T, Roncal C, Carmeliet P, Lambrechts D. J Cell Mol Med. 2008 Dec;12(6B):2533-51. PMID: 19210754

 Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 2007 Jun;8(6):464-78. PMID: 17522591

 Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003 Jun;9(6):685-93. PMID: 12778167

 Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003 Jun;9(6):677-84. PMID: 12778166

 Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003 Jun;9(6):653-60. PMID: 12778163

 van Beijnum JR, Eijgelaar WJ, Griffioen AW. Towards high-throughput functional target discovery in angiogenesis research. Trends Mol Med. 2005 Nov 30; PMID: 16325471

 Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med. 2003 Nov;3(7):643-51. PMID: 14601638

 Marchuk DA, Srinivasan S, Squire TL, Zawistowski JS. Vascular morphogenesis: tales of two syndromes. Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R97-112. PMID: 12668602

 Ribatti D, Vacca A, Nico B, Ria R, Dammacco F. Cross-talk between hematopoiesis and angiogenesis signaling pathways. Curr Mol Med. 2002 Sep;2(6):537-43. PMID: 12243246

 Brahimi-Horn C, Berra E, Pouyssegur J. Hypoxia: the tumor’s gateway to progression along the angiogenic pathway. Trends Cell Biol. 2001 Nov;11(11):S32-6. PMID: 11684440