Angiogenesis is the process whereby new blood vessels are formed. Physiological angiogenesis occurs in a variety of settings, including embryogenesis, wound healing and inflammation. Pathological angiogenesis may occur in such settings as tumor and atherosclerotic neovascularization. Endothelial cells exhibit remarkable plasticity and can rapidly transition to migratory and proliferative phenotypes. This phenotypic transformation not only changes cellular physiology, but also cellular metabolic requirements, and thus cellular metabolism.The proposed research focuses on understanding the metabolism of endothelial cells underlying physiological and pathological angiogenesis. By specifically targeting the metabolic energy supply of tumor microvasculature, we hope to be able to limit tumor growth and metastasis while minimizing side effects to normal cells. Conversely, we believe that this knowledge will allow us to promote physiological angiogenesis in such settings as wound healing and myocardial infarction.There is a great deal of heterogeneity within endothelial cells and their biological functions, as they must be specialized to deal with their specific environments and tissue interactions. Arterial endothelial cells are generally quiescent and are exposed to high oxygen and glucose concentrations, as they line the primary conduit for nutrient delivery in the circulatory system. On the other hand, venous endothelial cells are often in deoxygenated environments and can function in sprouting and transport. Finally, lymphatic endothelial cells are often in anoxic environments (lacking oxygen) and have been characterized to participate in lipid uptake, inflammation and metastasis.Thus, we hypothesize that there are fundamental differences in the basal metabolism of endothelial cells of arterial, venous and lymphatic origin. In this proposal, we aim to address the unknown but important questions of whether cellular metabolism defines the fate endothelial cells.