Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1a (PGC-1a) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1a in vascular function using mice with endothelial specific loss of function (PGC-1a EC KO) and endothelial specific gain of function (PGC-1a EC TG). Here we report that endothelial PGC-1a is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1a sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1a EC TG mice were protected. Mechanistically, PGC-1a 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-1a expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor a (ERRa) 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.

Read more »