Abstract 17339: Deficiency of Sirtuin 3 in Endothelium Reduces Endothelial-Dependent Relaxation and Impairs Myogenic Response in Coronary and Middle Cerebral Arteries of Mice

Abstract

Previously, we demonstrated that specific knockout of Sirtuin 3 (Sirt3) in endothelial cells (ECs) impairs coronary flow reserve and diastolic function in mice. So far, the role of endothelial Sirt3 in the coronary arteries remains unexplored. Male and female Sirt3 EC-knockout (Sirt3 EC KO) mice and Sirt3-Lox-P mice at 14-15-month old age were used to assess the roles of endothelial Sirt3 on the microvascular functions. Mouse coronary arteries (CA) and middle cerebral arteries (MCA) were isolated and mounted in a myograph system. Myogenic response was evaluated by increasing perfusion pressure. Ach (Acetylcholine, 1nM-100μM)-induced EC-dependent vasodilation and NO donor SNP (sodium nitroprusside,1nM-10μM)-induced EC-independent vasodilation were examined. Myogenic response was significantly impaired in both CA and MCA of male and female Sirt3 ECKO mice, as evidenced by a lack of constriction while raising perfusion pressure from 10 mmHg to 150 mmHg. Both wall thickness and cross-sectional area were increased in CA and MCA of male and female Sirt3 EC KO mice. The wall to lumen ratio was increased in MCA, but did not change in CA of Sirt3 EC KO mice, compared to SIRT3-Lox-p mice. The wall tension and myogenic tone were significantly decreased in CA and MCA of both male and female Sirt3 EC KO mice. The vessel stiffness was not significantly different between SIRT3EC KO mice and SIRT3-Lox-p mice. In CA, the Ach-induced EC-dependent vasodilation was reduced in both male and female Sirt3 ECKO mice. Intriguingly, the SNP-induced EC-independent vasodilation was significantly reduced in female Sirt3 ECKO mice, but did not observed in male Sirt3 ECKO mice. In MCA, the Ach-induced EC-dependent vasodilation was only impaired in male Sirt3 ECKO mice, but was not observed in female Sirt3 ECKO mice. Whereas, the SNP-induced EC-independent vasodilation was impaired in both male and female Sirt3 EC KO mice as compared to their control SIRT3-Lox-p mice. These data revealed a sex and organ specific role of Sirt3 in EC, i.e. there is more EC-independent dysfunction in female CA, but greater impairment of EC-dependent relaxation in male MCA. Our study demonstrates the critical role of endothelial Sirt3 in maintaining microvascular function in coronary and cerebral arteries.