Endothelial Progenitor Cell Recruitment in Diabetic Mice

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DESCRIPTION (provided by applicant): Diabetic patients have a defect in their ability to heal wounds and respond to ischemic stress. The mechanisms responsible for this compromised vascular regenerative capacity are poorly understood. Recently, endothelial precursor cells (EPCs) have been recognized to be recruited to sites of neovascularization. Preliminary work in our laboratory shows that diabetic mice (db/db, NOD, and streptozotocin-induced) are specifically deficient, compared to normal control mice, in their ability to mobilize and recruit endothelial precursor cells (EPCs) to wounds or ischemic limbs. An essential role for EPC recruitment in normal mice impairs both wound healing and the response to acute ischemia. This dysfunctional regenerative neovascularization in diabetic mice can be corrected by adenoviral-mediated overexpression of angiogenic growth factors, such as Angiopoietin-1 (Ang-1) which recruit EPCs that can correct diabetic wound healing impairment and the poor response to ischemia. The overall objective of our investigations is to understand the mechanisms by which EPCs are mobilized and recruited to target tissues in wound healing and in response to ischemia and understand how these mechanisms are impaired by diabetes. Our working hypothesis is that recruitment of bone marrow-derived EPCs is essential for triggering a rapid neovascularization response in a wound or ischemic tissue and that site-specific EPC recruitment is specifically deficient in diabetes. In order to test this hypothesis we plan experiments to achieve the following specific aims: 1. To demonstrate that mobilization and recruitment of growth factors 2. To determine the mechanism by which angiogenic growth factors mobilize and recruit bone marrow-derived EPCs to target areas of a wound or ischemic tissues 3. To determine the mechanisms by which EPCs orchestrate the local angiogenic response by interaction with resident cellular milieu.