Ca_V3.1 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 [Ca²⁺] is a key determinant of constriction, tied to L-type (Ca_V1.2) Ca²⁺ channels. While important, other Ca²⁺ channels, particularly T-type could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca²⁺ channel (Ca_V3.1) using C57BL/6 wild type and Ca_V3.1^-/- mice. Patch-clamp electrophysiology, pressure myography, blood pressure and Ca²⁺ imaging defined the Ca_V3.1^-/- phenotype relative to C57BL/6. Ca_V3.1^-/- mice had absent Ca_V3.1 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 Ca²⁺ wave generation, asynchronous events of Ca²⁺ release from the sarcoplasmic reticulum, insensitive to L-type Ca²⁺ channel blockade (Nifedipine, 0.3 µM). Proximity ligation assay (PLA) confirmed IP₃R1/Ca_V3.1 close physical association. IP₃R blockade (2-APB, 50 µM or xestospongin C, 3 µM) in nifedipine-treated C57BL/6 arteries rendered a Ca_V3.1^-/- contractile phenotype. Findings indicate that Ca²⁺ influx through Ca_V3.1 contributes to myogenic tone at hyperpolarized voltages through Ca²⁺-induced Ca²⁺ release tied to the sarcoplasmic reticulum. This study helps establish Ca_V3.1 as a potential therapeutic target to control blood pressure.