Diabetes is an enormous public health problem affecting 16 million Americans with 800,000 new cases each year. Type I diabetic patients have a defect in their angiogenic capacity 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. The principal investigators of this proposal, Timothy M Crombleholme, MD (a surgeon with a research interest in angiogenesis and vasculogenesis) and Robert M Cohen, MD (a Diabetologist with a research interest in the role of glycosylation in complications of diabetes) have formed a collaboration to study the impaired function of EPCs in murine models of type I diabetes. Preliminary work shows that NOD diabetic mice 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 EPCs is supported by our preliminary data showing that blockade of 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 which recruit EPCs. Our overall objective is to understand the mechanisms by which EPCs are mobilized and recruited to a target tissues in wound healing and in response to ischemia and understand how these mechanisms are impaired by type I 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 the following specific aims: 1. To demonstrate that mobilization and recruitment of bone marrow derived EPCs is compromised in type I diabetes. 2. To determine the mechanisms by which type I diabetes impairs angiogenic growth factors ability to mobilize and recruit bone marrow-derived EPCs to target areas of a wound or ischemic tissue. 3. To determine the mechanisms by which type I diabetes alters EPC gene expression and function.
