Regulation of angiogenesis by hypoxia: role of the HIF system

Abstract

The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.

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Figure 1: Dual regulation of HIF-α subunits by prolyl and asparaginyl hydroxylation.
Figure 2: Pathways linking angiogenesis to oxygen availability through the regulation of HIF.
Figure 3: Multiple interfaces of hypoxia pathways with the angiogenic growth factor VEGF.
Figure 4
Figure 5: Schematic illustrating the coselection of pathways in cancer.

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Correspondence to Peter J Ratcliffe.

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C.W.P. and P.J.R. are scientific cofounders of ReOx, Ltd.

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Pugh, C., Ratcliffe, P. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9, 677–684 (2003). https://doi.org/10.1038/nm0603-677

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