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 CaV3.2 channels restrain arterial constriction through a feedback response involving the large-conductance Ca2+-activated K+ channel (BKCa). 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-BKCa 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 Ni2+, a CaV3.2 blocker, to either constrict arteries or suppress T-type currents in CaV3.2−/− 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 CaV3.2 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 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-BKCa to hyperpolarize and relax arteries.
- calcium-activated potassium channels
- calcium channels
- calcium signaling
- ryanodine receptors
- T-type calcium channels
- vascular smooth muscle
- Received April 8, 2015.
- Accepted May 31, 2015.
- © 2015 American Heart Association, Inc.