Ca(V)3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries

The arterial myogenic response to intraluminal pressure elicits constriction to maintain tissue perfusion. Smooth muscle [Ca(2+)] is a key determinant of constriction, tied to L-type (Ca(V)1.2) Ca(2+) channels. While important, other Ca(2+) channels, particularly T-type could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca(2+) channel (Ca(V)3.1) using C57BL/6 wild type and Ca(V)3.1(−/−) mice. Patch-clamp electrophysiology, pressure myography, blood pressure and Ca(2+) imaging defined the Ca(V)3.1(−/−) phenotype relative to C57BL/6. Ca(V)3.1(−/−) mice had absent Ca(V)3.1 expression and whole-cell current, coinciding with lower blood pressure and reduced mesenteric artery myogenic tone, particularly at lower pressures (20–60 mmHg) where membrane potential is hyperpolarized. This reduction coincided with diminished Ca(2+) wave generation, asynchronous events of Ca(2+) release from the sarcoplasmic reticulum, insensitive to L-type Ca(2+) channel blockade (Nifedipine, 0.3 µM). Proximity ligation assay (PLA) confirmed IP(3)R1/Ca(V)3.1 close physical association. IP(3)R blockade (2-APB, 50 µM or xestospongin C, 3 µM) in nifedipine-treated C57BL/6 arteries rendered a Ca(V)3.1(−/−) contractile phenotype. Findings indicate that Ca(2+) influx through Ca(V)3.1 contributes to myogenic tone at hyperpolarized voltages through Ca(2+)-induced Ca(2+) release tied to the sarcoplasmic reticulum. This study helps establish Ca(V)3.1 as a potential therapeutic target to control blood pressure.