Inositol 1,4,5‐Trisphosphate Receptors Regulate Vascular Smooth Muscle Cell Proliferation and Neointima Formation in Mice

Abstract

Background Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca 2+ has been recognized as a key player. However, the physiological role of Ca 2+ release via inositol 1,4,5‐trisphosphate receptors (IP 3 Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined. Methods and Results Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP 3 Rs in regulating VSMC proliferation. Expression of all 3 IP 3 R subtypes was increased in cultured VSMCs upon platelet‐derived growth factor‐BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP 3 R subtypes abolished endoplasmic reticulum Ca 2+ release in cultured VSMCs, significantly reduced cell proliferation induced by platelet‐derived growth factor‐BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle–specific deletion of all IP 3 R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase‐9 expression in injured vessels. Mechanistically, IP 3 R‐mediated Ca 2+ release may activate cAMP response element–binding protein, a key player in controlling VSMC proliferation, via Ca 2+ /calmodulin‐dependent protein kinase II and Akt. Loss of IP 3 Rs suppressed cAMP response element–binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca 2+ permeable ionophore, ionomycin, can reverse cAMP response element–binding protein phosphorylation in IP 3 R triple knockout VSMCs. Conclusions Our results demonstrated an essential role of IP 3 R‐mediated Ca 2+ release from endoplasmic reticulum in regulating cAMP response element–binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.