Thursday 4 September 2003
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.
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.
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.
VEGF and VEGFRs
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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