IP₃ receptors regulate vascular smooth muscle contractility and hypertension

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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

Qingsong Lin, Guiling Zhao, Xi Fang, Xiaohong Peng, Huayuan Tang, Hong Wang, Ran Jing, Jie Liu, W. Jonathan Lederer, Ju Chen, Kunfu Ouyang