Depletion of mitochondrial CypD in endothelial and smooth muscle cells attenuates vascular dysfunction and hypertension.

Abstract

Hypertension is a major risk factor of cardiovascular disease affecting nearly half of adult population, but only 25% patients have their blood pressure under control. Hypertension is associated with mitochondrial dysfunction; however, its molecular mechanisms and causative role are still elusive. Understanding these mechanisms is important to develop new therapies. Cyclophilin D (CypD) promotes mitochondrial swelling and dysfunction. The objective of this study is to test if CypD depletion attenuates vascular dysfunction and hypertension. To test this hypothesis, we used endothelial-specific and smooth muscle-specific CypD knockout mice in angiotensin II model of vascular dysfunction and hypertension. Our results show that depletion of endothelial CypD prevents angiotensin II-induced impairment of endothelial-dependent vasorelaxation, preserves endothelial nitric oxide and mitochondrial respiration, reduces hypertension, vascular oxidative stress and vascular metabolic glycolytic-switch compared with wild-type littermates. Depletion of smooth muscle CypD slightly reduces angiotensin II-induced hypertension, partially attenuates reduction in vascular nitric oxide and vasorelaxation, abolishes vascular superoxide overproduction, diminishes angiotensin II-induced vascular glycolysis, hypertrophy and fibrosis. Our data showed an intriguing "metabolic" and "redox" crosstalk between endothelial and smooth muscle cells. Depletion of endothelial CypD reduces not only angiotensin II-induced endothelial glycolysis but also attenuates smooth muscle cell glycolytic switch. Interestingly, depletion of smooth muscle CypD was also not limited to the effect on smooth muscle glycolysis, but it also reduced endothelial cell glycolysis. Vascular oxidative stress was inhibited both in EcCypDKO and SmcCypDKO mice, therefore, cell-specific CypD depletion had a "global" antioxidant effect on the entire vasculature. Our results support a novel function of mitochondrial CypD in regulation of superoxide production and metabolism of vascular smooth muscle and endothelial cells which affect endothelial barrier and smooth muscle vascular functions. We suggest that blocking vascular CypD reduces vascular oxidative stress, improves vascular metabolism and vascular function which may be beneficial in cardiovascular disease.