Nerve growth factor – The key factor in endothelial aging, angiogenesis and gastric ulcer healing

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 DESCRIPTION (provided by applicant): Background/Rationale: Angiogenesis - formation of new capillary blood vessels is a fundamental process essential for healing of tissue injury, e.g. gastric erosions (GE) and ulcers (GU). Gastric mucosa of aging humans and rats (aging gastric mucosa) exhibits increased susceptibility to injury, impaired angiogenesis and delayed healing. [Our overall hypothesis is that nerve growth factor (NGF) is critical for gastric endothelial cell (EC) viability, function, angiogenesis and GU healing, and that NGF deficiency in aging ECs is the major mechanism of aging-related impairment of gastric angiogenesis and GU healing in aging individuals.] The rationale for this hypothesis stems from our preliminary studies showing that: 1) aging gastric ECs (AGECs) have reduced expression of NGF, and NGF protein and/or NGF gene therapy restores in vitro angiogenesis in aging ECs cells and reverses NSAIDs-induced inhibition of angiogenesis, and [2) local treatment of GU in aging rats with NGF significantly increases local expression of NGF and VEGF, angiogenesis, accelerates ulcer healing, and improves mucosal regeneration.] Our specific objectives are to determine whether and to what extent: 1) NGF and its signaling are critical for gastric ECs viability, function and angiogenesis and to identify the underlying molecular mechanisms; 2) NGF deficiency is: (a) crucial mechanism for ECs' aging and for aging-related impairment of EC proliferation and angiogenesis and (b) whether NGF treatment or NGF gene therapy restores in vitro angiogenesis in aging ECs; [3) Local treatment of GUs in aging rats with NGF will improve vascular regeneration and GU healing and whether these events can be visualized in vivo and in real time using confocal laser endomicroscopy (CLE).] Our long-term objective is to uncover novel mechanisms that regulate gastric angiogenesis and its impairment in aging, to provide a basis for the therapeutic use of NGF to improve angiogenesis and healing of GU in aging individuals and to use CLE for in vivo assessment of GU healing, vascular regeneration and for identifying GU scar abnormalities that may be the basis for the ulcer recurrence. Design: Since ECs are critical targets and effectors of angiogenesis, in in vitro studies in ECs isolated from gastric mucosa of young and aging rats we will determine the mechanisms underlying aging related impairment of EC functions, expression of NGF, VEGF, their receptors, PI3K/Akt and MAPK signaling, and the role of NGF in EC survival, migration, proliferation and angiogenesis. Next we will examine in vivo in aging and young rats sequential events of GU healing and vascular regeneration and will determine whether locally injected NGF will improve GU healing in aging rats and prevent NSAIDs-induced GU recurrence. We will also determine human relevance of our experimental findings using human specimens of GUs from young and aging individuals. Significance: The central topic of our project is neovascularization, injury healing and impact of aging. In 2006, ~39 million Americans (12% of population) were 65 years of age or older, and this number is projected to reach ~70 million by 2030. This population is at high risk of tissue and organ injuries, and GU complications. Impaired angiogenesis in aging is a key factor in delayed healing, morbidity and mortality. [Recent studies indicate that the incidence of non-H. pylori, non-NSAIDs ulcers ("idiopathic" ulcers) is increasing and they constitute up to 30% of all ulcers and patients with a history of "idiopathic" bleeding ulcers have a high risk of recurrent ulcer bleeding and a high mortality 83 - 92%. Therefore the GU recurrence and its complications still remain important clinical issue, especially in aging and severely ill patients.] The proposed studies will provide insight into novel mechanisms and the regulatory role of NGF and angiogenesis in GU healing and their relation to aging-related impairment of these processes. This novel information can be applicable to other areas of mucosal healing including inflammatory bowel disease, esophageal erosions and ulcers, as well as to cancer-related neovascularization.