We have identified a novel growth factor, Brain Derived Neurotrophic Factor (BDNF) that is highly expressedin the developing and adult coronary vasculature. BDNF binds to the TrkB receptor tyrosine kinase topromote chemotaxis and surival, and the p75 receptor to initiate apoptosis. Endothelial and vascular smoothmuscle cells (vSMC) in the developing and adult heart express TrkB, whereas p75 expression is morelimited to vessels in late gestation. In BDNF and TrkB gene-targeted animals, the initial vascular bed of theheart forms normally, but endothelial survival and vessel remodeling is perturbed in late gestation leading toperinatal lethality. Thus, we hypothesize that BDNF acts on TrkB-expressing endothelial and vSMC topromote stabilization of capillaries and arteries, whereas p75 directs remodeling and selective apoptosis ofthe immature vascular bed. Thus, we predict that the immature cardiac vasculature may initially becomposed of an excess channels, which undergo selective regression/apoptosis to generate appropriatelymatched arteries, capillaries and veins; we postulate that this phenomenon is recapitulated during adultneovascularization. Our recent studies also document that subsets of pro-angiogenic hematopoietic cells arerecruited to the neo-angiogenic niche and contribute to the assembly of the blood vessels during ischemicrevascularization. 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 peripheralcirculation in response to BDNF where VEGFRI+TrkB+cells contribute to neoangiogenesis in a femoralartery 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 cardiacrevascularization. These hypotheses will be tested in by addressing following aims:(1) Endothelial andsmooth muscle cell apoptosis accompanies coronary vascular remodeling; (2) Selective regression ofvascular channels, coupled with recruitment of marrow derived hematopoietic progenitors, promotes theformation of arteries, capillaries and veins in development, and in revascularization; (S)optimaladaptiveneovascularization in the ischemic heart requires BDNF-mediated recruitment ofVEGFR1+TrkB+progenitors. These studies will lay the foundation for clinical stragegies where BDNF aloneor 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 cardiacrevascularization in patients with myocardial ischemia.
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