ABSTRACT Diabetics suffer defective angiogenesis as a long-term complication and consequently a high propensity to develop critical limb ischemia (CLI), the leading cause of limb amputation worldwide. This is due, in significant part, to the deteriorated capacity of diabetic endothelial cells (ECs) and bone marrow-derived angiogenic cells, also called endothelial progenitor cells (EPCs) to properly elaborate needed blood vessels in ischemic areas. Lack of knowledge as to how this occurs has hampered therapeutic opportunities for CLI, including adoptive therapies with autologous EPCs. PPAR?-coactivator (PGC)-1? is a versatile regulator of gene transcription that coordinates broad metabolic programs in numerous tissues. The new and critical role for endothelial PGC-1? is now emerging. Diabetes induces PGC-1? in mouse ECs and human EPCs, which in turn activates Notch pathway that powerfully renders ECs resistant to VEGF. Ablation of EC PGC-1? in diabetic mice dramatically rescues the full angiogenic capacity, which highlights considerable promise of targeting PGC-1?-Notch axis to treat diabetic CLI. However, the significance of EC PGC-1? in diabetes is just beginning to be understood. Deeper knowledge of how exactly this pathway blunts EC and EPC functions is imperative to fully explore its therapeutic potential, since PGC-1? and Notch are expressed widely and mediate distinct, sometimes opposing effects among cell types. Burgeoning evidence indicates that ECs are highly glycolytic comparable to tumor cells, and that EC energy metabolism is the key mediator of sprouting angiogenesis in response to VEGF. In this proposal, we hypothesize that persistent angiogenic impairment of diabetes is, at least in part, mediated by PGC-1?/Notch-dependent alteration of cellular machineries that coordinate cytoskeleton with bioenergetics in ECs and EPCs, and that this mechanism is independent of previously recognized mediators of diabetic vascular dysfunction such as reactive oxygen species. Indeed, our preliminary findings identify novel downstream effectors of PGC-1?/Notch axis that strongly support our hypothesis, and that this regulator is surprisingly dispensable for health but required for diseases progression. This provides answers to many questions regarding the PGC-1? angiostatic mechanism, and opens avenues to develop safe and efficacious therapeutics for diabetic angiopathy that circumvent possible unwanted effects of targeting PGC-1?/Notch. Our hypothesis would thus be of translational relevance to innovate therapies, including gene delivery and adoptive EPCs transplantation, to salvage intractable dysfunction of ECs and EPCs in diabetes that causes angiogenic failure and CLI. Our concept would also provide clues to strategizing how to intervene in cell metabolism and cytoskeleton to develop therapeutics. The major goal of this proposal is to address this possibility.