Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 35, Issue 8, Pages 1843-1851Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.115.305736
Keywords
arteries; calcium-activated potassium channels; calcium channels; calcium signaling; ryanodine receptors; T-type calcium channels; vascular smooth muscle
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-69088]
- University of Western Ontario
- Alberta Innovates Health Solutions (AIHS)
- Medical Sciences
- AIHS
- Eyes High postdoctoral fellowship
- National Science Foundation [MRI-DBI 0923559]
- Loma Linda University School of Medicine
- USPHS (United States Public Health Service) [HD069746]
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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.
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