Regulation of angiogenesis by hypoxia and hypoxia-inducible factors.
Maintenance of oxygen homeostasis is critical for the survival of multicellular organs. As a result, both invertebrates and vertebrates have developed highly specialized mechanisms to sense changes in oxygen levels and to mount adequate cellular and systemic responses to these changes. Hypoxia, or low oxygen tension, occurs in physiological situations such as during embryonic development, as well as in pathological conditions such as ischemia, wound healing, and cancer. A primary effector of the adaptive response to hypoxia in mammals is the hypoxia-inducible factor (HIF) family of transcription regulators. These proteins activate the expression of a broad range of genes that mediate many of the responses to decreased oxygen concentration, including enhanced glucose uptake, increased red blood cell production, and the formation of new blood vessels via angiogenesis. This latter process is dynamic and results in the establishment of a mature vascular system that is indispensable for proper delivery of oxygen and nutrients to all cells in both normal tissue and hypoxic regions. Angiogenesis is essential for normal development and neoplastic disease as tumors must develop mechanisms to stimulate vascularization to meet increasing metabolic demands. The link between hypoxia and the regulation of angiogenesis is an area of intense research and the molecular details of this connection are still being elaborated. This chapter will provide an overview of current knowledge and highlight new insights into the importance of HIF and hypoxia in angiogenesis in both physiological and pathophysiological conditions.
Hickey
Michele M
MM
Department of Cell and Molecular Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia 19104, USA.
Simon
M Celeste
MC
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000503:physiopathology
D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1