Angiogenesis is a physiological process in which new blood vessels are formed to meet the oxygenation demands of local tissues. Thus, the identification of growth factors which specifically promote angiogenesis would provide a means to ameliorate the ischemic consequences of atherosclerosis occluding the arterial system. Although factors such as VEGF and bFGF appeared promising in pre-clinical trials, studies in humans have been mixed, prompting a search for additional factors with angiogenic activity. Here we propose to study the role of one of the neurotrophins, BDNF, in promoting collateral vessel formation in the ischemic heart and skeletal muscle. Best known as a differentiative and survival factor for neurons, we have recently identified BDNF as a critical regulator of cardiac vessel stabilization and survival through analysis of BDNF null mutant mice. In addition, BDNF inhibits angiogenic actions in nonischemic animal models. Although our long term goals are to determine whether BDNF can promote vessel formation in ischemic human myocardium, we propose three interrelated aims to identify the mechanisms by which BDNF promotes vessel growth and stability in animal models of vascular insufficiency. First, we will identify the actions of BDNF on purified microvascular endothelial cells, assessing chemotaxis, proliferation and survival, and will characterize the signaling pathways which regulate these events. Second, we will study the induction of BDNF in response to tissue ischemia, and identify the cell types which upregulate BDNF. Lastly, we will characterize the angiogenic response to BDNF, alone or in combination with VEGF in the well characterized models of hindlimb ischemia and coronary constriction to assess effects on capillary formation, ensheathment of vessels by vascular smooth muscle cells and vascular remodeling. These studies will allow us to determine whether local production of BDNF by skeletal or cardiac myocytes promotes vessel growth in ischemic tissue. In addition, these studies will test whether BDNF acts coordinately with VEGF to promote the stability of newly formed vessels.
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