The role of hypoxia‐inducible factor‐2 alpha in angiogenesis

Angiogenesis is a key enabling feature of mammalian embryonic development and tumor progression, which provides oxygen and nutrients that are required for vessel growth and tumor cell growth, respectively. Hypoxia is a driver of this phenomenon and is considered to be one of the most potent initiators of angiogenesis both in vitro and in vivo through stabilization of the transcription factors, hypoxia-inducible factor-1 and -2 (HIF-1 and HIF-2). Although these proteins are highly homologous, emerging evidence suggests that they have unique transcriptional targets and differential impact on angiogenesis. Although HIF-1α is the best known and widely described isoform, recent studies suggest that HIF-2α is a critical regulator of physiological and pathophysiological angiogenesis and, at least, the similiarly important as HIF-1α. Indeed, HIF-2α has been shown to regulate multiple aspects of angiogenesis, including cell proliferation, migration, maturation of blood vessels, and metastasis. In this review, we focus on recent insights into HIF-2α expression, activation, and function under hypoxic and nonhypoxic conditions. We also summarize the current knowledge on the crosstalk between HIF-2 and angiogenesis, describing reported phenotypical changes of HIF-2α genetic models and HIF-2 target genes implicated in angiogenesis. Finally, we provide a survey of recent pharmacologic strategies to specifically target HIF-2 activity.