We have identified a novel growth factor, Brain Derived Neurotrophic Factor (BDNF) that is highly expressed in the developing and adult coronary vasculature. BDNF binds to the TrkB receptor tyrosine kinase to promote chemotaxis and surival, and the p75 receptor to initiate apoptosis. Endothelial and vascular smooth muscle cells (vSMC) in the developing and adult heart express TrkB, whereas p75 expression is more limited to vessels in late gestation. In BDNF and TrkB gene-targeted animals, the initial vascular bed of the heart forms normally, but endothelial survival and vessel remodeling is perturbed in late gestation leading to perinatal lethality. Thus, we hypothesize that BDNF acts on TrkB-expressing endothelial and vSMC to promote stabilization of capillaries and arteries, whereas p75 directs remodeling and selective apoptosis of the immature vascular bed. Thus, we predict that the immature cardiac vasculature may initially be composed of an excess channels, which undergo selective regression/apoptosis to generate appropriately matched arteries, capillaries and veins;we postulate that this phenomenon is recapitulated during adult neovascularization. Our recent studies also document that subsets of pro-angiogenic hematopoietic cells are recruited to the neo-angiogenic niche and contribute to the assembly of the blood vessels during ischemic revascularization. These cells are recruited in response to VEGF-A and express the VEGF-receptor (VEGFR-1). Subsets of VEGFR1+cells also express functional TrkB and are mobilized to the peripheral circulation in response to BDNF where VEGFRI+TrkB+cells contribute to neoangiogenesis in a femoral artery model of hindlimb ischemia. Thus, we hypothesize that regenerating cardiac tissue provides for a pro- hemangiogenic microenvironment that is permissive and instructive for recruitment and incorporation ofpro- angiogenic VEGFR1-TrkB+ hemotopoietic cells, to support adaptive remodeling during cardiac revascularization. These hypotheses will be tested in by addressing following aims:(1) Endothelial and smooth muscle cell apoptosis accompanies coronary vascular remodeling;(2) Selective regression of vascular channels, coupled with recruitment of marrow derived hematopoietic progenitors, promotes the formation of arteries, capillaries and veins in development, and in revascularization;(S)optimaladaptive neovascularization in the ischemic heart requires BDNF-mediated recruitment of VEGFR1+TrkB+progenitors. These studies will lay the foundation for clinical stragegies where BDNF alone or in combination with VEGF-A will be used to promote neo-antiogenesis after myocardial infarction. Similarly, VEGFR1+TrkB+ cells can be developed in therapeutic cellular cardiomyoplasty to restore cardiac revascularization in patients with myocardial ischemia.
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