EFFECTS OF AGING ON BLOOD-DERIVED ENDOTHELIAL CELLS

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This proposal is in response to program objective 5 - Stems Cells, Tissue Repair, and Cell Replacement in Aging. Our goal is to determine if impairment of blood-derived endothelial cell precursors (angioblasts) contributes to cardiovascular disease associated with aging. In this study we will determine if the ability of adult blood-derived angioblasts to differentiate, proliferate, and incorporate into the vasculature is altered by aging. Blood-derived angioblasts appear to function in the routine maintenance of vascular endothelium, and in some models of angiogenesis, as many as 10% of endothelial cells in the neovasculature are blood-derived. Angioblasts are related or identical to hematopoietic stem cells. Hematopoietic stem cell proliferative ability and possibly cell number decrease with age, suggesting that angioblasts might be similarly affected by aging. Additionally, angioblast function is altered in diabetes, and numerous and severe cardiovascular complications are associated with diabetes. Based on these and related findings, we hypothesize that aging impairs angioblast function. This impairment may contribute to vascular problems associated with aging. To test our hypothesis we will 1) compare the ability of angioblasts derived from young and older adults to proliferate and differentiate in Vitro, and 2) determine if aging influences the extent to which blood-derived cells incorporate into the neovasculature. The latter experiments will be accomplished by injecting human angioblasts into mice undergoing angiogenesis due to hindlimb ischemia. In this study we will answer three questions. First, does blood derived from umbilical cords, young adults, and older adults carry the same angioblastic potential? Secondly, is the ability of angioblasts to incorporate into the neovasculature of aged mice impaired? Thirdly, do angioblasts derived from older adults have a reduced capacity to incorporate into the neovasculature or to improve blood flow in ischemic mice? In answering these questions will ascertain whether aging alters several aspects of angioblast function, including the ability to restore blood flow to ischemic tissue. Reduced angioblast function would suggest that angioblasts play a role in aging associated cardiovascular complications, and that angioblasts may be an important target for therapies designed to prevent or correct.