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

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. Previous studies have identified multiple mitochondrial pathways linked to hypertension including apoptosis, calcium homeostasis, mitochondrial metabolism, and oxidative stress. Several enzymes can serve as “master” regulators of mitochondrial function such PGC-1α, NRF1, and Sirt3. A new potential “master” regulator, Cyclophilin D (CypD), is implicated in the hypertension-associated mitochondrial pathways listed above. CypD is implicated in both mitochondrial homeostasis and mitochondrial dysfunction. It is, therefore, unclear if CypD inhibition is protective or detrimental to vascular functions. We hypothesized that cell-specific CypD depletion in endothelial and smooth muscle cells attenuates vascular dysfunction and hypertension. To test this hypothesis, we have developed tamoxifen-inducible endothelial-specific CypD knock out mice (Ec CypDKO ) and tamoxifen-inducible smooth muscle cell-specific CypD knock out mice (Smc CypDKO ). We performed studies of angiotensin II (AngII)-induced hypertension, endothelial-dependent relaxation, endothelial-barrier permeability, vascular superoxide production, vascular mitochondrial respiration and glycolysis, aortic hypertrophy, and fibrosis. It was found 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 the 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 Ec CypDKO and Smc CypDKO mice, therefore, cell-specific CypD depletion had a “global” antioxidant effect on the entire vasculature. These data support the novel function of mitochondrial CypD in the regulation of superoxide production and metabolism of vascular smooth muscle and endothelial cells which affect endothelial barrier and smooth muscle vascular functions. Mitochondria have tremendous metabolic plasticity, and our data suggest that CypD is dispensable in adult homeostatic functions. We suggest that conditional CypD depletion or pharmacological inhibition of CypD can be effectively compensated by other mitochondrial pathways. Blocking CypD can prevent CypD switch from homeostatic to pathogenic “gain-of-function” in pathological conditions and, therefore, reduce vascular oxidative stress, improve vascular metabolism and vascular function which can be beneficial in cardiovascular disease. This work was funded by National Institutes of Health (R01HL144943, RO1HL157583) and American Heart Association Awards (23TPA1077648, 24TPA1300869). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.