The broad, long-term objective of this proposal is to identify angiogenic pathways that are involved in selective mobilization and recruitment of bone marrow (BM)-derived endothelial and hematopoietic stem and progenitor cells thereby dictating heterogeneity of organ-specific vasculature. In particular, we plan to determine the mechanism by which the expression of Vascular Endothelial Growth Factor-receptors, VEGFR2 (Flk-1, KDR), VEGFR1 (Flt-1) and VEGFR3 (Flt-4) orchestrate proliferation, mobilization and incorporation of BM-derived progenitors into organ-specific neo-vasculature during regenerating processes, including lung regeneration and BM hemangiogenic reconstitution. We have shown that VEGF family of angiogenic factors promote recruitment of CD133+VEGFR2+ endothelial progenitor cells (EPCs) from BM to the angiogenic neo-vessels. We have also demonstrated that functional VEGFR1 is expressed on the subsets of hematopoietic stem and progenitors cells (HSPCs) supporting mobilization of these cells from BM. Co-recruitment of angio-competent VEGFR1+HSPCs to the neo-angiogenic vessels facilitate incorporation of VEGFR2+EPCs into functional neo-vessels. Mobilization of BM-derived progenitor cellsl is a dynamic process and requires recruitment of these cells from unique BM niches. Angiogenic factors, induce expression of metalloproteinase-9 (MMP-9), which in turn promote the release of soluble Kit-ligand (sKitL). Increase in bio-available sKitL enhance cycling and proliferation of HSPCs, setting up the stage for mobilization to the circulation. BM also contains a population of CD133+VEGFR3+ lymphatic EPCs that could possibly contribute to lymphangiogenesis. Based on these studies, we hypothesize that regenerating lung and BM provide for a pro-hemangiogenic microenvironment that is permissive for recruitment and incorporation of angio-competent BM-derived progenitors. Organ-specific angiogenic factors promote mobilization and recruitment of VEGFR2+ and VEGFR3+ EPCs to the neo-vessels. Co-recruitment of the VEGFR1+ hematopoietic cells facilitate functional incorporation of vascular progenitors and dictate vascular heterogeneity in the initial phases of organ regeneration. This hypothesis through studying the following specific aims: We plan to determine temporal, spatial and regional recruitment patterns of BM-derived progenitors during tissue revascularization-remodeling and compare their incorporation pattern in transgenic mice with diminished hemangiogenic potential including, VEGF164/164, VEGF189/189, PIGF-/-, and Id1+/-Id3-/- mice. Define the role of VEGFR1, VEGFR2 and VEGFR3 signaling in the regulation of mobilization, homing and recruitment of progenitors to the pulmonary and BM vasculature. Assess the physiological significance and contribution of BM-derived CD133+VEGFR2+, CD133+VEGFR3+EPCs and VEGFR1+HSPCs to revascularization during organ regeneration. These studies will lay the foundation for using BM-marrow derived cells for therapeutic cell therapy to enhance organ (i.e. lung, marrow) revascularization.
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