Mechanisms of adaptive angiogenesis to tissue hypoxia.

Angiogenesis is mostly an adaptive response to tissue hypoxia, which occurs under a wide variety of situations ranging from embryonic development to tumor growth. In general, angiogenesis is dependent on the accumulation of hypoxia inducible factors (HIFs), which are heterodimeric transcription factors of alpha and beta subunits. Under normoxia, HIF heterodimers are not abundantly present due to oxygen dependent hydroxylation, polyubiquitination, and proteasomal degradation of alpha subunits. Under hypoxia, however, alpha subunits are stabilized and form heterodimers with HIF-1beta which is not subject to oxygen dependent regulation. The accumulation of HIFs under hypoxia allows them to activate the expression of many angiogenic genes and therefore initiates the angiogenic process. In recent years, however, it has become clear that various other mechanisms also participate in fine tuning angiogenesis. In this review, I discuss the relationship between hypoxia and angiogenesis under five topics: (1) regulation of HIF-alpha abundance and activity by oxygen tension and other conditions including oxygen independent mechanisms; (2) hypoxia-regulated expression of angiogenic molecules by HIFs and other transcription factors; (3) responses of vascular cells to hypoxia; (4) angiogenic phenotypes due to altered HIF signaling in mice; and (5) role of the HIF pathway in pathological angiogenesis. Studies discussed under these topics clearly indicate that while mechanisms of oxygen-regulated HIF-alpha stability provide exciting opportunities for the development of angiogenesis or anti-angiogenesis therapies, it is also highly important to consider various other mechanisms for the optimization of these procedures.