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Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1843-51. doi: 10.1161/ATVBAHA.115.305736. Epub 2015 Jun 11.

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

Author information

1
From the Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, University of Calgary, Calgary, Alberta, Canada (O.F.H., S.E.B., A.Z., D.G.W.); Department of Pharmacology and Toxicology, Alexandria University, Alexandria, Egypt (O.F.H.); Department of Basic Sciences, Division of Pharmacology, Loma Linda University, CA (M.R., S.M.W.); Department of Pharmacology, University of California, Davis (J.L.P.); and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (D.G.W.).
2
From the Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, University of Calgary, Calgary, Alberta, Canada (O.F.H., S.E.B., A.Z., D.G.W.); Department of Pharmacology and Toxicology, Alexandria University, Alexandria, Egypt (O.F.H.); Department of Basic Sciences, Division of Pharmacology, Loma Linda University, CA (M.R., S.M.W.); Department of Pharmacology, University of California, Davis (J.L.P.); and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (D.G.W.). dwelsh@ucalgary.ca.

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 (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 Ni(2+), 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 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-BKCa to hyperpolarize and relax arteries.

KEYWORDS:

T-type calcium channels; arteries; calcium channels; calcium signaling; calcium-activated potassium channels; ryanodine receptors; vascular smooth muscle

PMID:
26069238
PMCID:
PMC5117108
DOI:
10.1161/ATVBAHA.115.305736
[Indexed for MEDLINE]
Free PMC Article

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