Hui Wang1, Ze Yuan1, Bianbian Wang2, Bochuan Li1, Huizhen Lv1, Jinlong He1, Yaqian Huang3, Zhen Cui1, Qiannan Ma1, Ting Li4, Yi Fu3, Xiaoli Tan5, Yangping Liu5, Shengpeng Wang4, Changhe Wang2, Wei Kong3, Yi Zhu1. 1. Tianjin Key Laboratory of Metabolic Diseases; Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, China (H.W., Z.Y., B.L., H.L., J.H., Z.C., Q.M., Y.Z.). 2. Neuroscience Research Center, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, China (B.W., C.W.). 3. Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China (Y.H., Y.F., W.K.). 4. Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (T.L., S.W.). 5. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, China (X.T., Y.L.).
Abstract
BACKGROUND: Vascular endothelial cells are critical for maintaining blood pressure (BP) by releasing biologically active molecules, such as nitric oxide. A non-endothelial cell resident matricellular protein, COMP (cartilage oligomeric matrix protein), plays a pivotal role in maintaining cardiovascular homeostasis, but little is known about its regulatory effect on BP. METHODS: Mice were infused with AngII (angiotensin II; 450 ng/kg per minute) for 3 days via an osmotic minipump, and BP was monitored by a tail-cuff system. Second-order mesenteric arteries were isolated from mice for microvascular tension measurement. Nitric oxide was detected by an electron paramagnetic resonance technique. Small-interfering RNA transfection, co-immunoprecipitation, bioluminescence resonance energy transfer assays, and patch-clamp electrophysiology experiments were used for further detailed mechanism investigation. RESULTS: COMP-/- mice displayed elevated BP and impaired acetylcholine-induced endothelium-dependent relaxation compared with wild-type mice with or without AngII. Inhibition of eNOS (endothelial nitric oxide synthase) abolished the difference in endothelium-dependent relaxation between wild-type and COMP-/- mice. Furthermore, COMP directly interacted with the C-terminus of Piezo1 via its C-terminus and activated the endogenous Piezo1 currents, which induced intracellular Ca2+ influx, Ca2+/calmodulin-dependent protein kinase type II and eNOS activation, and nitric oxide production. The Piezo1 activator, Yoda1, reduced the difference in endothelium-dependent relaxation and BP in wild-type and COMP-/- mice. Moreover, COMP overexpression increased eNOS activation and improved endothelium-dependent relaxation and BP. CONCLUSIONS: Our study demonstrated that COMP is a novel Piezo1 regulator that plays a protective role in BP regulation by increasing cellular Ca2+ influx, eNOS activity, and nitric oxide production.
BACKGROUND: Vascular endothelial cells are critical for maintaining blood pressure (BP) by releasing biologically active molecules, such as nitric oxide. A non-endothelial cell resident matricellular protein, COMP (cartilage oligomeric matrix protein), plays a pivotal role in maintaining cardiovascular homeostasis, but little is known about its regulatory effect on BP. METHODS: Mice were infused with AngII (angiotensin II; 450 ng/kg per minute) for 3 days via an osmotic minipump, and BP was monitored by a tail-cuff system. Second-order mesenteric arteries were isolated from mice for microvascular tension measurement. Nitric oxide was detected by an electron paramagnetic resonance technique. Small-interfering RNA transfection, co-immunoprecipitation, bioluminescence resonance energy transfer assays, and patch-clamp electrophysiology experiments were used for further detailed mechanism investigation. RESULTS: COMP-/- mice displayed elevated BP and impaired acetylcholine-induced endothelium-dependent relaxation compared with wild-type mice with or without AngII. Inhibition of eNOS (endothelial nitric oxide synthase) abolished the difference in endothelium-dependent relaxation between wild-type and COMP-/- mice. Furthermore, COMP directly interacted with the C-terminus of Piezo1 via its C-terminus and activated the endogenous Piezo1 currents, which induced intracellular Ca2+ influx, Ca2+/calmodulin-dependent protein kinase type II and eNOS activation, and nitric oxide production. The Piezo1 activator, Yoda1, reduced the difference in endothelium-dependent relaxation and BP in wild-type and COMP-/- mice. Moreover, COMP overexpression increased eNOS activation and improved endothelium-dependent relaxation and BP. CONCLUSIONS: Our study demonstrated that COMP is a novel Piezo1 regulator that plays a protective role in BP regulation by increasing cellular Ca2+ influx, eNOS activity, and nitric oxide production.