Regulation of angiogenesis by oxygen sensing mechanisms

The choices for blood vessels to undergo angiogenesis or stay quiescent are mostly determined by the status of tissue oxygenation. A major link between tissue hypoxia and active angiogenesis is the accumulation of hypoxia-inducible factor (HIF)-alpha subunits which play a major role in the transcriptional activation of genes encoding angiogenic factors. HIF-alpha abundance is negatively regulated by a subfamily of dioxygenases referred to as prolyl hydroxylase domain-containing proteins (PHDs) which use O(2) as a substrate to hydroxylate HIF-alpha subunits and hence tag them for rapid degradation. Under hypoxic conditions, HIF-alpha subunits accumulate due to reduced hydroxylation efficiency and form transcriptionally active heterodimers with HIF-1ss to activate the expression of angiogenic factors and other proteins important for cellular adaptation to hypoxia. Angiogenesis is regulated by a combination of at least two different mechanisms. The paracrine mechanism is mediated by non-endothelial expression of angiogenic factors such as vascular endothelial growth factor (VEGF)-A, which in turn interact with endothelial cell surface receptors to initiate angiogenic activities. In the autocrine mechanism, endothelial cell themselves are induced to express VEGF-A, which collaborate with the paracrine mechanism to support angiogenesis and protect vascular integrity. Because of critical roles of PHDs and HIFs in regulating angiogenic activities, studies are underway to assess their candidacy as targets for angiogenesis therapies.