Genetic ablation of CaV3.2 channels enhances the arterial myogenic response by modulating the RyR-BKCa axis

Abstract

Objective - In resistance arteries, there is an emerging view that smooth muscle CaV3.2 channels restrain arterial constriction through a feedback response involving the large-conductance Ca 2+ -activated K + channel (BK Ca). Here, we used wild-type and CaV3.2 knockout (CaV3.2 -/-) mice to definitively test whether CaV3.2 moderates myogenic tone in mesenteric arteries via the CaV3.2-ryanodine receptor-BK Ca axis and whether this regulatory mechanism influences blood pressure regulation. Approach and Results - Using pressurized vessel myography, CaV3.2 -/- mesenteric arteries displayed enhanced myogenic constriction to pressure but similar K + -induced vasoconstriction compared with wild-type C57BL/6 arteries. Electrophysiological and myography experiments subsequently confirmed the inability of micromolar Ni 2+, a CaV3.2 blocker, to either constrict arteries or suppress T-type currents in CaV3.2 -/- smooth muscle cells. The frequency of BK Ca -induced spontaneous transient outward K + currents dropped in wild-type but not in knockout arterial smooth muscle cells upon the pharmacological suppression of CaV3.2 channel. Line scan analysis performed on en face arteries loaded with Fluo-4 revealed the presence of Ca 2+ sparks in all arteries, with the subsequent application of Ni 2+ only affecting wild-type arteries. Although CaV3.2 channel moderated myogenic constriction of resistance arteries, the blood pressure measurements of CaV3.2 -/- and wild-type animals were similar. Conclusions - Overall, our findings establish a negative feedback mechanism of the myogenic response in which CaV3.2 channel modulates downstream ryanodine receptor-BK Ca to hyperpolarize and relax arteries.