Background Endothelial NO synthase plays a central role in regulating vasodilation and blood pressure. Intracellular Ca²⁺ mobilization is a critical modulator of endothelial NO synthase function, and increased cytosolic Ca²⁺ concentration in endothelial cells is able to induce endothelial NO synthase phosphorylation. Ca²⁺ release mediated by 3 subtypes of inositol 1,4,5-trisphosphate receptors ( IP ₃Rs) from the endoplasmic reticulum and subsequent Ca²⁺ entry after endoplasmic reticulum Ca²⁺ store depletion has been proposed to be the major pathway to mobilize Ca²⁺ in endothelial cells. However, the physiological role of IP ₃Rs in regulating blood pressure remains largely unclear. Methods and Results To investigate the role of endothelial IP ₃Rs in blood pressure regulation, we first generated an inducible endothelial cell-specific IP ₃R1 knockout mouse model and found that deletion of IP ₃R1 in adult endothelial cells did not affect vasodilation and blood pressure. Considering all 3 subtypes of IP ₃Rs are expressed in mouse endothelial cells, we further generated inducible endothelial cell-specific IP ₃R triple knockout mice and found that deletion of all 3 IP ₃R subtypes decreased plasma NO concentration and increased basal blood pressure. Furthermore, IP ₃R deficiency reduced acetylcholine-induced vasodilation and endothelial NO synthase phosphorylation at Ser1177. Conclusions Our results reveal that IP ₃R-mediated Ca²⁺ release in vascular endothelial cells plays an important role in regulating vasodilation and physiological blood pressure.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	125
2	Pharmacology	1	1	125
3	Analytical Chemistry	1	1	125
4	Andrology	1	1	125
5	Chromatography	1	1	125

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