VEGF and Islet Vascularization

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DESCRIPTION (provided by applicant): Pancreatic islets are extensively vascularized and this is important in their ability to sense the blood glucose and quickly secrete insulin. While islets receive up to 20 times more blood flow than surrounding pancreatic acinar tissue, the molecular factors and mechanisms responsible for islet vascularization are incompletely defined. New experimental evidence indicates that pancreatic islets express a number of angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin (Ang), and ephrins, and that interactions between islet and endothelial cells are important in both islet development and vascularization. Pancreatic islet transplantation is an emerging therapy for type 1 diabetes, but major obstacles and gaps in our scientific knowledge preclude islet transplantation from being widely adapted. For example, islet isolation severs vascular connections that must be reestablished through angiogenesis/vasculogenesis; a large number of islets (perhaps the majority) die in the first days after transplantation while islet revascularization is occurring. VEGF is a crucial angiogenic factor in vascular development, angiogenesis in response to ischemia, and tumor-related angiogenesis. Even though pancreatic endocrine and exocrine cells share a common developmental lineage, islet cells have greater VEGF expression and vessel density than surrounding exocrine cells. To test the hypotheses that islet vascularization and revascularization requires production of VEGF-A by pancreatic islet cells, we will: 1) Elucidate the role of VEGF-A in pancreatic islet development and function using cell-specific, temporal inactivation of the VEGF-A gene using the Cre-loxP system. 2) Examine how gain or loss of VEGF-A function in pancreatic islets affects islet development and function. 3) Determine if gain or loss of VEGF-A function alters the revascularization, survival, or function of transplanted islets. These results should provide a better understanding of normal islet vascularization and how this affects normal islet development, architecture, and function. Information from the transplantation studies may suggest new therapeutic strategies to improve the rapidity and degree of revascularization of transplanted islets.