Abstract 19681: Endothelial PGC-1alpha Mediates Vascular Dysfunction in Diabetes

[Background] Endothelial dysfunction and aberrant angiogenesis is a hallmark of diabetes. How metabolic perturbations deteriorate endothelial function, however, still remains elusive. The transcriptional coactivator PPARgamma-coactivator-1alpha (PGC-1alpha) is a powerful regulator of metabolism in numerous cell types and is involved in the development of diabetes, but its role in endothelial cells remains poorly understood. [Objective] We hypothesized that PGC-1alpha may mediate endothelial dysfunction and aberrant neovascularization associated with diabetes. [Methods and Results] PGC-1alpha mRNA was upregulated by two to fivefold in cultured endothelial cells (ECs) following high glucose stimulation as well as in the ECs isolated from distinct diabetic mouse models (streptozocin-induced type I DM, high fat diet (HFD) feeding, and ob/ob mice). Forced expression of PGC-1alpha abolished VEGF and S1P-induced EC migration, and diminished the capacity of EPCs to undergo vasculogenesis. Conversely, pro-angiogenic factors like VEGF, sphingosine 1-phosphate (S1P) and NO rapidly downregulated PGC-1alpha in ECs, suggesting a role for PGC-1alpha in angiogenic signaling. Consistently, deletion of PGC-1alpha caused pronounced EC migration to a level comparable to that provoked by VEGF. Mechanistically, the angiostatic effect of PGC-1alpha was mediated through inhibition of Rac1 and Akt/eNOS pathway. Transgenic overexpression of PGC-1alpha in ECs in vivo recapitulated multiple diabetic phenotypes, including aberrant reendothelialization in response to carotid injury, wound healing, and blood flow recovery in response to hindlimb ischemia. Conversely, deletion of PGC-1alpha in ECs rescued wound healing dysfunction in type I and II diabetic animals, and restored blood flow recovery in type I diabetic animals with hindlimb ischemia. [Conclusion] Our data identify EC PGC-1alpha as a critical negative regulator of endothelial function and angiogenesis. Upregulation of PGC-1alpha by hyperglycemia renders ECs unable to properly undergo angiogenesis, and thus constitutes a critical mechanism underlying vascular dysfunction in diabetes.