title: IP3receptors regulate vascular smooth muscle contractility and hypertension.
abstract: Inositol 1, 4, 5-trisphosphate receptor-mediated (IP3R-mediated) calcium (Ca2+) release has been proposed to play an important role in regulating vascular smooth muscle cell (VSMC) contraction for decades. However, whether and how IP3R regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle-specific IP3R triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IP3R-mediated Ca2+release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction. We demonstrated that deletion of IP3Rs significantly reduced aortic contractile responses to vasoconstrictors, including phenylephrine, U46619, serotonin, and endothelin 1. Deletion of IP3Rs also dramatically reduced the phosphorylation of MLC20 and MYPT1 induced by U46619. Furthermore, although the basal blood pressure of smTKO mice remained similar to that of wild-type controls, the increase in systolic blood pressure upon chronic infusion of angiotensin II was significantly attenuated in smTKO mice. Taken together, our results demonstrate an important role for IP3R-mediated Ca2+release in VSMCs in regulating vascular contractility and hypertension.
authors: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors: Qingsong
authors: Q
authors: Lin
authors: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Guiling
authors: G
authors: Zhao
authors: University of California San Diego, School of Medicine, Department of Medicine, La Jolla, California, USA.
authors: Xi
authors: X
authors: Fang
authors: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors: Xiaohong
authors: X
authors: Peng
authors: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors: Huayuan
authors: H
authors: Tang
authors: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors: Hong
authors: H
authors: Wang
authors: Xiangya Hospital, Central South University, Changsha, China.
authors: Ran
authors: R
authors: Jing
authors: Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China.
authors: Jie
authors: J
authors: Liu
authors: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: W Jonathan
authors: WJ
authors: Lederer
authors: University of California San Diego, School of Medicine, Department of Medicine, La Jolla, California, USA.
authors: Ju
authors: J
authors: Chen
authors: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors: Kunfu
authors: K
authors: Ouyang
mesh_terms: D000818:Animals; D001794:Blood Pressure; D020013:Calcium Signaling; D006973:Hypertension / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D014662:Vasoconstrictor Agents