IP receptors regulate vascular smooth muscle contractility and hypertension.

Inositol 1, 4, 5-trisphosphate receptor-mediated (IPR-mediated) calcium (Ca) release has been proposed to play an important role in regulating vascular smooth muscle cell (VSMC) contraction for decades. However, whether and how IPR regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle-specific IPR triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IPR-mediated Ca release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction. We demonstrated that deletion of IPRs significantly reduced aortic contractile responses to vasoconstrictors, including phenylephrine, U46619, serotonin, and endothelin 1. Deletion of IPRs 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 IPR-mediated Ca release in VSMCs in regulating vascular contractility and hypertension.