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 Ca2+ has been recognized as a key player. However, the physiological role of Ca2+ release via inositol 1,4,5‐trisphosphate receptors (IP3Rs) 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 IP3Rs in regulating VSMC proliferation. Expression of all 3 IP3R 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 IP3R subtypes abolished endoplasmic reticulum Ca2+ 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 IP3R 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, IP3R‐mediated Ca2+ release may activate cAMP response element–binding protein, a key player in controlling VSMC proliferation, via Ca2+/calmodulin‐dependent protein kinase II and Akt. Loss of IP3Rs suppressed cAMP response element–binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca2+ permeable ionophore, ionomycin, can reverse cAMP response element–binding protein phosphorylation in IP3R triple knockout VSMCs. Conclusions Our results demonstrated an essential role of IP3R‐mediated Ca2+ release from endoplasmic reticulum in regulating cAMP response element–binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.

Keywords

• Ca2+ signaling
• cell proliferation
• IP3 receptor
• neointima formation
• vascular remodeling
• vascular smooth muscle cell