Critical role of hypoxia sensor--HIF-1α in VEGF gene activation. Implications for angiogenesis and tissue injury healing.
Vascular injury of esophageal and gastrointestinal mucosa caused by injurious and ulcerogenic factors leads to the cessation of blood flow, ischemia, and hypoxia and tissue necrosis in form of erosions or ulcers. The re-establishment of blood vessels through the process of angiogenesis--formation of new blood vessels--is critical for healing of tissue injury because is essential for delivery of oxygen and nutrients to the healing site. Hypoxia increases expression of hypoxia inducible factor (HIF-1), which serves as hypoxia sensor and activates compensatory and adaptive mechanisms. However, the molecular mechanisms and the role of HIF-1α in hypoxia-driven cellular and molecular events of angiogenesis in gastrointestinal injury healing have not been fully explored. The review discusses the novel molecular mechanisms of angiogenesis in gastric and esophageal mucosa with focus on HIF1α and VEGF interactions during healing of gastric mucosal injury and esophageal ulcers. HIF-1α is upregulated by gastric mucosal injury and esophageal ulcers; this upregulation correlates with VEGF gene activation and initiation of angiogenesis. The non-steroidal anti-inflammatory drugs (NSAIDs) interfere with hypoxia-induced HIF-1α accumulation, VEGF gene activation and angiogenesis through upregulation of von Hippel- Lindau (VHL) tumor suppressor, which activates degradation of HIF-1α protein. HIF-1α is a transcription factor that under hypoxic conditions, accumulates in endothelial cells and can bind to VEGF gene promoter and induce VEGF gene expression. In order to activate the VEGF gene, HIF-1α must be transported to the nucleus. Recent evidence implicates importins as key mechanism in this process.
VA Long Beach Healthcare System & the University of California, Irvine, 5901 E. 7th Street, Long Beach, CA 90822-5201, USA. amrita.ahluwalia@va.gov
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Tarnawski
D000818:Animals; D005767:Gastrointestinal Diseases / Q000473:pathology / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D028884:Karyopherins / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D014945:Wound Healing / Q000502:physiology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D028884:Karyopherins; D042461:Vascular Endothelial Growth Factor A