The islet contains a dense vascular structure of several features. The expression of vascular endothelial growth factor (VEGF)-A in beta cells is indispensable for the formation of this structure. Thus, the beta cell-specific VEGF-A-deficient mouse (RIP-Cre:Vegf(fl/fl)) is useful for studying the role of the islet vasculature on the function of islets and regulation of beta cell mass. Studies using RIP-Cre:Vegf(fl/fl) mice revealed that defects in the normal vascular structure are associated with abnormal insulin secretion and concluded that the islet vascular system is essential for normal insulin secretion into the blood stream. On the other hand, whereas the endothelial cells might be involved in regulation of islet mass and the mouse model of diabetes shows that the number of endothelial cells correlate with the islet mass, RIP-Cre:Vegf(fl/fl) mice show almost normal response of islet expansion in the presence of insulin resistance. However, whereas bone marrow transplantation induces islet expansion in control mice, it does not induce the proper expansion of beta cell mass in RIP-Cre:Vegf(fl/fl) mice. These data indicate that the roles of VEGF-A and islet vasculature in the regulation of beta cell mass depends on the stimulus for the islets.