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      IP3 receptors regulate vascular smooth muscle contractility and hypertension.

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          Abstract

          Inositol 1, 4, 5-trisphosphate receptor-mediated (IP3R-mediated) calcium (Ca(2+)) 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 Ca(2+) 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 Ca(2+) release in VSMCs in regulating vascular contractility and hypertension.

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          Author and article information

          Journal
          JCI Insight
          JCI insight
          American Society for Clinical Investigation
          2379-3708
          2379-3708
          Oct 20 2016
          : 1
          : 17
          Affiliations
          [1 ] Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
          [2 ] Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
          [3 ] University of California San Diego, School of Medicine, Department of Medicine, La Jolla, California, USA.
          [4 ] Xiangya Hospital, Central South University, Changsha, China.
          [5 ] Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China.
          Article
          89402
          10.1172/jci.insight.89402
          5070959
          27777977

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