PGC-1α dictates endothelial function through regulation of eNOS expression

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1 alpha (PGC-1 alpha) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1 alpha in vascular function using mice with endothelial specific loss of function (PGC-1 alpha EC KO) and endothelial specific gain of function (PGC-1 alpha EC TG). Here we report that endothelial PGC-1 alpha is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1 alpha sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1 alpha EC TG mice were protected. Mechanistically, PGC-1 alpha promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1 alpha expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor a (ERR alpha) is required to coordinate the PGC-1a-induced eNOS expression. In conclusion, endothelial PGC-1a expression protects from vascular dysfunction by promoting NO. bioactivity through ERRa induced expression of eNOS.