IP3 receptors regulate vascular smooth muscle contractility and hypertension
Qingsong Lin, … , Ju Chen, Kunfu Ouyang
Qingsong Lin, … , Ju Chen, Kunfu Ouyang
Published October 20, 2016
Citation Information: JCI Insight. 2016;1(17):e89402. https://doi.org/10.1172/jci.insight.89402.
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Research Article Vascular biology

IP3 receptors regulate vascular smooth muscle contractility and hypertension

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

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Figure 2

Loss of IP3Rs reduced vascular contractile responses to various vasoconstrictors.

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Loss of IP3Rs reduced vascular contractile responses to various vasocons...
Thoracic aortas and the first-order branch of superior mesenteric arteries were isolated from control (Ctrl) and smTKO mice. The vessels were cut into 2-mm-long segments, and myographic measurements were performed. (A) Reference contraction of aortic rings induced by high potassium (100 mM) in control and smTKO mice. n = 6–11 mice per group. Significance was determined by the 2-tailed, unpaired Student’s t test. In the box-and-whisker plot, the center lines indicate the mean and the upper and lower bounds of the boxes represent the 25th–75th percentiles of the averaged data. (B–E) Tension induced by phenylephrine (PE), U46619, 5-hydroxytryptamine (5-HT), and endothelin 1 (ET1) in control and smTKO aortic rings. (F–J) Tension induced by PE, U46619, 5-HT, ET1, and angiotensin II (AngII) in control and smTKO mesenteric arteries. n = 6 mice per group. For all dose-response curves, data were expressed as a percentage of the peak of K+-induced contraction, and significance was determined by 2-way ANOVA analysis with Bonferroni post-hoc test. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control. Data represent mean ± SEM.