Effective neovascularization, or new blood vessel formation, is critical for both wound healing and tissue survival following ischemia. Neovascularization occurs via two distinct pathways: the sprouting of new blood vessels from existing vessels (angiogenesis) and the recruitment, proliferation and assembly of bone-marrow derived vascular progenitor cells into new vessels (vasculogenesis). Through complex signaling mechanisms, ischemic tissue (the soil) actively recruits circulating progenitor cells (the seeds) out of the bone marrow and into the area of ischemia to initiate proliferation and differentiation of these cells into new blood vessels. We and others have shown that aging significantly impairs this communication between ischemic tissue and circulating progenitor cells and leads to dysfunctional vasculogenesis. In aged patients, this dysfunction hinders recovery from ischemic insults such as myocardial infarction or stroke and impairs wound healing, which leads to poor clinical outcomes. In this proposal, we will capitalize on our laboratory's expertise by focusing on impaired wound healing as a representative example of dysfunctional vasculogenesis in aging. During the prior funding period, we demonstrated that aging markedly diminishes the activity of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1a), resulting in reduced expression of multiple vasculogenic genes and a dysfunctional response to ischemia. It is our fundamental hypothesis that dysfunction in HIF-1a-mediated neovascularization underlies the vascular complications of aging, and that identification and reversal of this dysfunction will improve recovery from ischemia in aged patients. In this proposal, we will expand on our previous findings to precisely define the causative mechanisms underlying HIF-1a dysfunction in hypoxic tissue (SA1), determine the role of increased oxidative stress in age-related dysfunctional vasculogenesis (SA2), and refine a therapeutic strategy to restore normal neovascularization to aged patients (SA3).