Intraluminal pressure‐induced constriction of resistance arteries is facilitated by activation of reverse‐mode Na + /Ca 2+ exchanger NCX1

Intracellular Ca 2+ is a vital second messenger that plays a fundamental role in regulating intraluminal pressure‐ and agonist‐induced vasoconstriction. Recently, our laboratory demonstrated that intraluminal pressure and G‐protein coupled receptor agonist stimulation activate p90 ribosomal S6 kinase 2 (RSK2). RSK2, in turn, phosphorylates the regulatory light chain of myosin (RLC 20 ) to induce constriction of small, resistance‐sized arteries. We also showed that RSK2 phosphorylates an active site on the Na + /H + exchanger (NHE‐1), leading to intracellular alkalization, increased cytosolic Ca 2+ [Ca 2+ ] i , and vasoconstriction. However, the mechanism by which activated NHE‐1 increases smooth muscle Ca 2+ and contractility is unclear. We hypothesize that RSK2‐mediated activation of NHE‐1 increases intracellular Na + , thereby activating the reverse mode of the plasma membrane Na + /Ca 2+ exchanger (NCX1) and increasing intracellular Ca 2+ . To test this hypothesis, we performed pressure myography and confocal Ca + imaging in pressurized 4 th ‐ and 5 th ‐order mesenteric arteries (MAs) isolated from mice. Our data shows that the intraluminal pressure‐induced constriction of MAs is significantly attenuated by the NCX1 inhibitor SEA0400. Additionally, SEA0400 evoked dilation in pressurized MAs pre‐constricted with thromboxane A2 receptor agonist U46619. Furthermore, we found that pressure‐induced increase in the number of smooth muscle cell Ca 2+ transients is significantly attenuated by SEA0400 in MAs. Our findings suggest that NCX1 contributes to pressure‐induced increases in smooth muscle Ca 2+ transients, ultimately contributing to pressure‐induced constriction. In combination with the reports of increased RSK and NHE‐1 activity in animal models of hypertension and hypertensive patients, our study provides a deeper understanding of the RSK2/NHE1/NCX signaling cascade and its contribution to vasoconstriction, vascular resistance, and blood pressure regulation.