IP ₃ receptors regulate vascular smooth muscle contractility and hypertension

Abstract

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.

Abstract

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.