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.

In this paper we reviewed and updated current views on the cellular and molecular mechanisms of gastric and esophageal ulcer healing. Gastric ulcer healing encompasses inflammation, cell proliferation, epithelial regeneration, gland reconstruction, formation of granulation tissue, neovascularization (new blood vessel formation), interactions between various cells and the matrix and tissue remodeling, resulting in scar formation. All these events are controlled by the cytokines and growth factors, GI hormones including gastrin, CCK, and orexigenic peptides such as ghrelin, orexin-A and obestatin as well as Cox2 generated prostaglandins. These growth factors and hormones trigger cell proliferation, migration, and survival utilizing Ras, MAPK, PI-3K/AKT, PLC-γ and Rho/Rac/actin signaling pathways. Hypoxia triggers activation of some of these genes (e.g., VEGF) via hypoxia inducible factor (HIF). Growth factors: EGF, HGF, IGF-1, their receptors and Cox2 are important for epithelial cell proliferation, migration, re-epithelialization and regeneration of gastric glands during gastric ulcer healing. Serum response factor (SRF) is also essential for re-epithelialization and muscle restoration. VEGF, bFGF, angiopoietins, nitric oxide, endothelin, prostaglandins and metalloproteinases are important for angiogenesis, vascular remodeling and mucosal regeneration within gastric ulcer scar. SRF is critical limiting factor for VEGF-induced angiogenesis. Esophageal ulcer healing follows similar pattern to gastric ulcer, but KGF and its receptor are the key players in regeneration of the epithelium. In addition to local mucosal cells from viable mucosa bordering necrosis, circulating bone marrow derived stem and progenitor cells are potentially important for ulcer healing, contributing to the regeneration of epithelial and connective tissue components and neovascularization.

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This paper reviews and updates current views on gastric mucosal injury with a focus on the microvascular endothelium as the key target and the role of the anti-apoptosis protein survivin. Under normal conditions, mucosal integrity is maintained by well structured and mutually amplifying defense mechanisms, which include pre-epithelial "barrier"--the first line of defense; and, an epithelial "barrier". Other important defense mechanisms of gastric mucosa include: continuous epithelial cell renewal, blood flow through mucosal microvessels (providing oxygen and nutrients), an endothelial microvascular "barrier," sensory innervation, and generation of PGs, nitric oxide and hydrogen sulfide. The microvascular endothelium lining gastric mucosal blood microvessels severs not only as a barrier but is a biologically active tissue involved in many synthetic and metabolic functions. It allows transport of oxygen and nutrients, and produces prostaglandins and leukotriens, procoagulant factors, nitric oxide, endothelin, ghrelin, HSP, growth factors such VEGF, bFGF, angiopoietin 2 and others, specific types of collagen, plasminogen activator, and can also actively contract. Accumulating evidence indicates that the gastric microvascular endothelium is a critical target for injury by ethanol, NSAIDs, free radicals, ischemia-reperfusion and other damaging factors. The injury--microvessel rupture, plasma and erythrocyte extravasation, platelet aggregation and fibrin deposition caused by these damaging factors--occurs early (1-5 min), precedes glandular epithelial cell injury and results in cessation of blood flow, ischemia, hypoxia and impaired oxygen and nutrient transport. As a consequence, mucosal necrosis develops. One of the main reasons for the increased susceptibility of gastric microvascular endothelial (vs. epithelial) cells to injury is reduced expression levels of survivin, an anti-apoptosis protein, which is a regulator of both proliferation and cell survival.

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