Inositol 1,4,5‐Trisphosphate Receptors in Endothelial Cells Play an Essential Role in Vasodilation and Blood Pressure Regulation

BACKGROUND: Endothelial NO synthase plays a central role in regulating vasodilation and blood pressure. Intracellular Ca(2+) mobilization is a critical modulator of endothelial NO synthase function, and increased cytosolic Ca(2+) concentration in endothelial cells is able to induce endothelial NO synthase phosphorylation. Ca(2+) release mediated by 3 subtypes of inositol 1,4,5‐trisphosphate receptors (IP (3)Rs) from the endoplasmic reticulum and subsequent Ca(2+) entry after endoplasmic reticulum Ca(2+) store depletion has been proposed to be the major pathway to mobilize Ca(2+) in endothelial cells. However, the physiological role of IP (3)Rs in regulating blood pressure remains largely unclear. METHODS AND RESULTS: To investigate the role of endothelial IP (3)Rs in blood pressure regulation, we first generated an inducible endothelial cell–specific IP (3)R1 knockout mouse model and found that deletion of IP (3)R1 in adult endothelial cells did not affect vasodilation and blood pressure. Considering all 3 subtypes of IP (3)Rs are expressed in mouse endothelial cells, we further generated inducible endothelial cell–specific IP (3)R triple knockout mice and found that deletion of all 3 IP (3)R subtypes decreased plasma NO concentration and increased basal blood pressure. Furthermore, IP (3)R deficiency reduced acetylcholine‐induced vasodilation and endothelial NO synthase phosphorylation at Ser1177. CONCLUSIONS: Our results reveal that IP (3)R‐mediated Ca(2+) release in vascular endothelial cells plays an important role in regulating vasodilation and physiological blood pressure.