Atherosclerosis represents an aberrant, continuous reparative inflammatory process in response to repeated injuries to the vessel wall. Indeed, the cardiovascular system is continuously exposed to a multitude of insults whose impact cumulates with the passage of time. Two sources of cells participating in the repair process exist: (1) local, differentiated, vascular endothelial and smooth muscle cells that migrate from adjacent vessel segments; and (2) recruited stern cells/vascular progenitor cells from the bone marrow, via peripheral circulation. We have recently discovered that chronic administration of whole bone marrow (BM) cells significantly reduced atherosclerotic lesion formation in an established mouse model of atherosclerosis --ApoE -/- C57/B6 mice fed high fat cholesterol, Western-type diet--even in the absence of restoration of ApoE gene expression and normalization of plasma cholesterol levels (>1200 mg/dl). Furthermore, BM cells from young, but not old, ApoE-/- mice were capable of vascular rejuvenation and atherosclerosis prevention. This data underscores the importance of stem cells/vascular progenitor cells in vascular healing and atherogenesis and provide support for the use of stern/progenitor cell therapy as a novel preventative and/or treatment strategy for atherosclerosis, particularly for individuals whose bone marrow, and its obsolescence, represents the bottleneck for long-term integrity of the cardiovascular system. In this project, we propose to test the hypothesis that after a lifetime of repairing atherosclerotic arteries, the supply of the specific type(s) of vascular progenitor cells (VPCs) needed to maintain the homeostasis of the cardiovascular system is somehow exhausted or these cells are functionally impaired. If the VPC """"""""spare parts"""""""" can be outsourced, the repair process can be boosted at appropriate intervals and atherosclerotic consequences delayed, perhaps indefinitely.
Specific Aim 1 : To determine the quantitative composition (FACS analysis), progeny functional characteristics, and gene expression phenotype (microarray analysis) of whole bone marrow cells or lineage negative side population (lin-SP) cells obtained from young versus old (wild-type, and ApoE -/-) mice;
Specific Aim 2 : To establish that competent VPCs are encompassed in the lin-SP fraction in the marrow, which convey the anti-atherosclerotic efficacy, by testing the effects of unfractionated bone marrow cells, enriched linSP cells and bone marrow cells deprived of lin-SP fraction obtained from young versus old (wild-type and ApoE -/-) mice in suppressing elevated plasma levels of chemo-cytokines and growth factors and in preventing atherosclerotic lesion formation in ApoE -/- mice;
Specific Aim 3 : To determine within the lin-SP fraction of young apoE -/- and wild-type BM the relative efficacy of a) candidate VPCs (CVPC, cells that are either depleted or functionally impaired in aging mice) isolated using markers identified in Aim 1, b) unfractionated lin-SP cells minus CVPCs (USP-CVPC), and c) unfractionated linSP cells (USP) in suppressing elevated plasma levels of IL-6, VEGF and other inflammatory markers and in preventing atherosclerosis in ApoE -/- mice;
and Specific Aim 4 : To determine the role of a4-integrin, VCAM-1, and E-selectin in mediating the engraftment of vascular progenitor cells to chronically injured vessel wall in apoE-/- mice. As a corollary, the relative contribution of cell engraftment versus a non-cell autonomous mechanism to vascular repair will be characterized.
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