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-1 alpha 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 HIF1 alpha and VEGF interactions during healing of gastric mucosal injury and esophageal ulcers. HIF-1 alpha 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-1 alpha accumulation, VEGF gene activation and angiogenesis through upregulation of von Hippel-Lindau (VHL) tumor suppressor, which activates degradation of HIF-1 alpha protein. HIF-1 alpha 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-1 alpha must be transported to the nucleus. Recent evidence implicates importins as key mechanism in this process.