Genetic ablation of CaV3.2 channels enhances the arterial myogenic response by modulating the RyR-BKCa axis.
Genetic ablation of CaV3.2 channels enhances the arterial myogenic response by modulating the RyR-BKCa axis.
复制标题
DOI：
10.1161/atvbaha.115.305736
复制
发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Welsh DG
中科院分区：
文献类型：
--
作者：
Harraz OF;Brett SE;Zechariah A;Romero M;Puglisi JL;Wilson SM;Welsh DG
在阻力动脉中，有一种新观点认为平滑肌 CaV3.2 通道通过涉及大电导 Ca2+ 激活 K+ 通道 (BKCa) 的反馈反应来抑制动脉收缩。在这里，我们使用野生型和 CaV3.2 敲除 (CaV3.2−/−) 小鼠来明确测试 CaV3.2 是否通过 CaV3.2-ryanodine 受体-BKCa 轴调节肠系膜动脉的肌源张力，以及这种调节机制是否影响血压调节。使用加压血管肌电图，CaV3.2−/−肠系膜动脉与野生型C57BL/6动脉相比，表现出增强的肌原性收缩，但K+诱导的血管收缩相似。电生理学和肌电图实验随后证实，微摩尔 Ni2+（一种 CaV3.2 阻滞剂）无法收缩动脉或抑制 CaV3.2−/− 平滑肌细胞中的 T 型电流。在药物抑制 CaV3.2 通道后，BKCa 诱导的自发瞬时外向 K+ 电流的频率在野生型中下降，但在敲除动脉平滑肌细胞中则没有下降。对装载 Fluo-4 的正面动脉进行的线扫描分析显示，所有动脉中都存在 Ca2+ 火花，随后应用 Ni2+ 仅影响野生型动脉。尽管CaV3.2通道调节阻力动脉的肌源性收缩，但CaV3.2−/−和野生型动物的血压测量结果相似。总体而言，我们的研究结果建立了肌源性反应的负反馈机制，其中 CaV3.2 通道调节下游兰尼碱受体 -BKCa 以使动脉超极化和松弛。
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. 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. 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.