Modulation of vascular gene expression by hypoxia

Abstract

Angiogenesis and inflammation are important features in atherosclerotic plaque destabilization. The transcription factors hypoxia-inducible factor-1alpha and Notch are key regulators of angiogenesis. In addition, hypoxia-inducible factor-1alpha has been linked to regulation of inflammatory processes and innate immunity. This review will document how hypoxia-inducible factor-mediated signaling pathways are initiated in hypoxic cells, and how the hypoxia-inducible factor and Notch-dependent signaling pathways are functionally integrated. Activation of the hypoxia-inducible factor-mediated signaling events by hypoxia is complex and regulated by a cascade of molecular events that will be reviewed in detail. The activated form of hypoxia-inducible factor enhances Notch-dependent activation of Notch target genes, thereby providing a mechanism by which hypoxia can regulate the differentiation status of a cell. Recent observations implicate the Notch signaling pathway in proper specification of cell identity, position and behavior in a developing blood vessel sprout, and the hypoxia-inducible factor-mediated signaling pathway is critical for induction of expression of vascular endothelial growth factor. Hypoxia-inducible factor and Notch transcription factors represent potentially attractive targets for regulation of angiogenesis and possibly inflammation. In view of the pleiotropic effects of these transcription factors, however, successful targeting of these signaling pathways will require the development of gene specific (and possibly tissue-specific) modulators and extensive validation in relevant model systems.