title: 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 (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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Osama F
authors.initials: OF
authors.lastname: Harraz
authors.affiliation: 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.).
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Brett
authors.affiliation: 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.).
authors.forename: Anil
authors.initials: A
authors.lastname: Zechariah
authors.affiliation: 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.).
authors.forename: Monica
authors.initials: M
authors.lastname: Romero
authors.affiliation: 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.).
authors.forename: Jose L
authors.initials: JL
authors.lastname: Puglisi
authors.affiliation: 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.).
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
authors.affiliation: 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.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Welsh
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D020013:Calcium Signaling; D025461:Feedback, Physiological; D005260:Female; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C530995:BKCa protein, mouse; C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D019837:Ryanodine Receptor Calcium Release Channel
keywords: T-type calcium channels; arteries; calcium channels; calcium signaling; calcium-activated potassium channels; ryanodine receptors; vascular smooth muscle