Requirement of TNFR p75 in ischemia-induced angiogenesis

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DESCRIPTION (provided by applicant): Background: Aging is a risk factor for development of coronary and peripheral artery diseases. The extent of ischemic damage and functional recovery in case of extensive impairment of vascularization is largely depending on the development of new collateral vessels. Tumor necrosis factor alpha (TNF-a), a macrophage/monocyte-derived pluripotent mediator and pro-inflammatory cytokine is expressed in ischemic areas and reported to induce angiogenesis. TNF has been reported to induce the expression of many angiogenesis related genes, through two different TNF receptors, TNFR1 (p55) and TNFR2 (p75). In various vascular ECs, TNF increased the expression of angiogenic factors VEGF, bFGF, IL-8, however, the role of two distinct TNF receptors in mediating these responses are still unclear. Hypothesis: p55 is largely known to mediate cytotoxic effects of TNF, whereas signaling through p75 is mostly implied in protective effects of TNF-alpha and because aging is associated with increased expression of p55 and decreased expression of p75 in cells from aged humans we hypothesized that the p75 may be essential in angiogenic signaling in adults. Purpose: 1) Determine the contribution of TNFR2 p75 on VEGF and bFGF gene expression on EC function in vitro and on angiogenesis in vivo; TNF-induced pro-angiogenic signaling and EC function is mediated, in large part, through p75 TNFR2. 2) Determine molecular mechanisms underlying TNF-mediated ischemia-induced survival and apoptosis signaling in ECs; In the absence of TNFR2 p75 post-ischemic apoptotic signaling is exaggerated. 3) Determine to what extent ischemia-induced mobilization, migration and recruitment of EPCs from bone marrow depends on signaling through p75 TNFR2; a) Ischemia-induced mobilization of EPCs from bone marrow is mediated, at least in part, via TNFR2 p75; b) Functional TNFR2 p75 is necessary for proper contribution of bone marrow-derived EPCs to post-ischemic recovery. Significance: the goal of this proposal is to define certain molecular mechanisms of iscmemia-induced TNF- mediated angiogenic signaling that may be impaired in adult tissue, in part, due to age-associated decrease in TNFR2 p75 expression. In addition, this proposal may lead to an identification of a gene target, which can be used to improve the poor recovery and prevent the development of severe ischemia-induced damage in adult coronary and peripheral vascular diseases.