Inositol 1, 4, 5-trisphosphate receptor–mediated (IP 3R-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 IP 3R regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle–specific IP 3R triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IP 3R-mediated Ca 2+ release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction. We demonstrated that deletion of IP 3Rs significantly reduced aortic contractile responses to vasoconstrictors, including phenylephrine, U46619, serotonin, and endothelin 1. Deletion of IP 3Rs 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 IP 3R-mediated Ca 2+ release in VSMCs in regulating vascular contractility and hypertension.
IP3R-mediated Ca2+ release in VSMCs plays an important regulatory role in vascular contractility and hypertension, as revealed by a smooth muscle specific-IP3R knockout mouse model.