Genetic Ablation of CaV3.2 Channels Enhances the Arterial Myogenic Response by Modulating the RyR-BKCa Axis. Issue 8 (August 2015)

• Record Type: Journal Article
• Authors: Harraz, Osama F.; Brett, Suzanne E.; Zechariah, Anil; Romero, Monica; Puglisi, Jose L.; Wilson, Sean M.; Welsh, Donald G.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 35:Issue 8(2015)
• Publication Date: 2015-08
• Subjects: Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.115.305736
• Languages: English
• ISSNs: 1079-5642

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objective—</title> <p>In resistance arteries, there is an emerging view that smooth muscle Ca<sub>V</sub>3.2 channels restrain arterial constriction through a feedback response involving the large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channel (BK<sub>Ca</sub>). Here, we used wild-type and Ca<sub>V</sub>3.2 knockout (Ca<sub>V</sub>3.2<sup>−/−</sup>) mice to definitively test whether Ca<sub>V</sub>3.2 moderates myogenic tone in mesenteric arteries via the Ca<sub>V</sub>3.2-ryanodine receptor-BK<sub>Ca</sub> axis and whether this regulatory mechanism influences blood pressure regulation.</p> </sec> <sec> <title>Approach and Results—</title> <p>Using pressurized vessel myography, Ca<sub>V</sub>3.2<sup>−/−</sup> mesenteric arteries displayed enhanced myogenic constriction to pressure but similar K<sup>+</sup>-induced vasoconstriction compared with wild-type C57BL/6 arteries. Electrophysiological and myography experiments subsequently confirmed the inability of micromolar Ni<sup>2+</sup>, a Ca<sub>V</sub>3.2 blocker, to either constrict arteries or suppress T-type currents in Ca<sub>V</sub>3.2<sup>−/−</sup> smooth muscle cells. The frequency of BK<sub>Ca</sub>-induced spontaneous transient outward K<sup>+</sup> currents dropped in wild-type but not in knockout arterial smooth muscle cells upon the pharmacological suppression of Ca<sub>V</sub>3.2 channel. Line scan analysis performed on en face arteries loaded with Fluo-4 revealed the presence of Ca<sup>2+</sup> sparks in all arteries, with the subsequent application of Ni<sup>2+</sup> only affecting wild-type arteries. Although Ca<sub>V</sub>3.2 channel moderated myogenic constriction of resistance arteries, the blood pressure measurements of Ca<sub>V</sub>3.2<sup>−/−</sup> and wild-type animals were similar.</p> </sec> <sec> <title>Conclusions—</title> <p>Overall, our findings establish a negative feedback mechanism of the myogenic response in which Ca<sub>V</sub>3.2 channel modulates downstream ryanodine receptor-BK<sub>Ca</sub> to hyperpolarize and relax arteries.</p> </sec> </abstract>