In the events leading to type 2 diabetes, inadequate compensatory increase of the beta cells mass could be a direct consequence of vascular disease, either by endothelial dysfunction or secondary to defective secretion of angiogenic peptides by beta cells. To dissect the role of angiogenic process in the maintenance and growth of islets, we studied pancreatic chimeras, consisting of endocrine chick cells and murine endothelial cells, obtained by grafting embryonic chick pancreas in SCID mice. We analyzed angiogenesis during development of the pancreatic chimera and examined the impact of hyperglycemia on the vasculature of the pancreas. We then used an avian-specific retrovirus, the RCAS system, to over-express VEGF during pancreatic development. Materials and methods: Seven-week-old female SCID mice were made diabetic by a single intra-peritoneal injection of streptozotocin (160mg/kg). Embryonic chick pancreases (E14) were grafted under the kidney capsule of SCID mice and collected 14 days later. Pancreatic vasculature was analyzed by immunohistochemistry using nestin, a mouse-specific endothelial marker, and in situ hybridization with both mouse- and chick-specific VEGFR-2 probes. Expression of angiopoïetin-2 (Ang2), thrombospondin-1 (Tsp1) and VEGF was analyzed by in situ hybridization. To over-express VEGF, an avian-specific retrovirus RCAS carrying the gene encoding the VEGF (RCAS-VEGF) was prepared. Chick pancreases were infected in vitro with the RCAS-VEGF for 1 hour before graft. Mammalian cells were not susceptible to the RCAS infection. All analyzes were performed on n=5 animals. This study was carried out along the principles of laboratory animal care. Results: As compared to normoglycemia, hyperglycemia increased beta-cell density (p<0.05). Pancreatic vasculature was disorganized with large bloodfilled spaces and vessels discontinuities. Vessel density was decreased as evidenced by quantification of nestin- and VEGFR-2-positive cells (p< 0.05). Expression of two anti-angiogenic factors, Tsp1 and Ang2 was increased in grafts (p<0.05), whereas no clear difference was observed for VEGF. In order to correct the vascular defects, we over-expressed VEGF in pancreas. In normoglycemic condition, number of both beta- and endothelial-cells was not altered by VEGF over-expression. In hyperglycemic conditions, number of both beta- and endothelial-cells was increased by VEGF over-expression (p<0.05). Ang2 and Tsp1 determinations are pending. Conclusion: Hyperglycemia induced major defects of the pancreatic vasculature associated with Ang2 and Tsp1 over-expression. These two anti-angiogenic growth factors have been associated with vasculopathy in diabetes. We demonstrated for the first time up-regulation of Ang2 expression in the pancreas in hyperglycemic conditions. In normoglycemic condition, there was no change after VEGF over-expression, whereas in hyperglycemic condition, VEGF over-expression increased both endocrine and endothelial cells.