Genetic Ablation of CaV3.2 Channels Enhances the Arterial Myogenic Response by Modulating the RyR-BKCa Axis

Objective In resistance arteries, there is an emerging view that smooth muscle Ca(V)3.2 channels restrain arterial constriction through a feedback response involving the large-conductance Ca2+-activated K+ channel (BKCa). Here, we used wild-type and Ca(V)3.2 knockout (Ca(V)3.2(-/-)) mice to definitively test whether Ca(V)3.2 moderates myogenic tone in mesenteric arteries via the Ca(V)3.2-ryanodine receptor-BKCa axis and whether this regulatory mechanism influences blood pressure regulation. Approach and Results Using pressurized vessel myography, Ca(V)3.2(-/-) 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 Ni2+, a Ca(V)3.2 blocker, to either constrict arteries or suppress T-type currents in Ca(V)3.2(-/-) smooth muscle cells. The frequency of BKCa-induced spontaneous transient outward K+ currents dropped in wild-type but not in knockout arterial smooth muscle cells upon the pharmacological suppression of Ca(V)3.2 channel. Line scan analysis performed on en face arteries loaded with Fluo-4 revealed the presence of Ca2+ sparks in all arteries, with the subsequent application of Ni2+ only affecting wild-type arteries. Although Ca(V)3.2 channel moderated myogenic constriction of resistance arteries, the blood pressure measurements of Ca(V)3.2(-/-) and wild-type animals were similar. Conclusions Overall, our findings establish a negative feedback mechanism of the myogenic response in which Ca(V)3.2 channel modulates downstream ryanodine receptor-BKCa to hyperpolarize and relax arteries.