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Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization
  1. Gregg L Semenza
  1. Institute for Cell Engineering, Department of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  1. Correspondence to Gregg Semenza, Miller Research Bldg, Suite 671, 733 N. Broadway, Baltimore, MD 21205, USA; gsemenza{at}jhmi.edu

Abstract

When tissue perfusion is impaired, the resulting reduction in O2 availability activates hypoxia-inducible factor 1 (HIF-1), which mediates increased transcription of genes encoding multiple angiogenic factors including vascular endothelial growth factor, stromal-derived factor 1, placental growth factor, and angiopoietins, leading to the mobilization of bone marrow-derived angiogenic cells, increased angiogenesis, and arterial remodeling. These HIF- 1-dependent responses are impaired by aging or loss of function mutations at the locus encoding the HIF-1α subunit. in mouse models of limb ischemia and lung transplant rejection, the augmentation of HIF-1 activity by gene therapy or chemical inducers was associated with maintenance of tissue perfusion that prevented limb amputation and allograft rejection, respectively. Thus, targeting HIF-1 may be of therapeutic benefit in these clinical contexts and others in which impaired tissue perfusion plays a role in disease pathogenesis.

  • angiogenesis
  • arteriogenesis
  • bronchiolitis obliterans
  • critical limb ischemia
  • desferrioxamine
  • dimethyloxalylglycine
  • prolyl hydroxylases

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