Crucial importance of the endothelial K+ channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction
Crucial importance of the endothelial K+ channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction
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DOI：
10.1096/fj.10-158956
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发表时间：
2010-09-01
期刊：
影响因子：
4.8
通讯作者：
de Wit, Cor
中科院分区：
文献类型：
--
作者：
Milkau, Malte;Kohler, Ralf;de Wit, Cor
骨骼肌活动需要血流量的大幅增加，而潜在的血管舒张涉及内皮活动，但内皮依赖性超极化因子（EDHF）的贡献尚不清楚。在 EDHF 信号传导中，由 Ca2+ 激活的 K+ 通道 SK3 和 IK1 介导的内皮超极化是关键步骤，并且还启动间隙连接依赖性传导扩张。我们评估了 SK3、IK1 和 connexin40 (Cx40) 在肌肉收缩引起的体内微循环扩张中的作用。迄今为止，使用活体显微镜在缺乏 SK3、IK1 或 Cx40 的麻醉小鼠的电刺激提睾骨骼肌中观察到小动脉。 SK3 的遗传缺陷（而非 IK1）会强烈减弱肌肉收缩的扩张。同样，特定阻断剂 UCL1684 对 SK3 的药理学阻断会损害野生型和 IK1 缺陷小鼠的这种扩张。相反，IK1 是乙酰胆碱诱导的扩张所必需的。 Cx40 的遗传缺陷也会减弱肌肉收缩引起的扩张，但不会减弱乙酰胆碱引起的扩张。这些数据支持这样的概念：通过激活 SK3 导致内皮超极化导致运动充血，并且超极化通过 Cx40 形成的间隙连接上升血管树以协调扩张。 SK3 和 IK1 缺乏对不同刺激的扩张的不同影响表明这些内皮通道的刺激依赖性激活。-Milkau, M., Kohler, R., de Wit, C. 内皮 K+ 通道 SK3 和连接蛋白 40 在骨骼肌收缩期间小动脉扩张中的至关重要性。 FASEB J. 24, 3572-3579 (2010)。 www.fasebj.org
Skeletal muscle activity requires substantial increases in blood flow, and the underlying vasodilation involves endothelial activity, but the contribution of the endothelium-dependent hyperpolarizing factor (EDHF) is only poorly defined. In EDHF signaling, endothelial hyperpolarization mediated by the Ca2+-activated K+ channels SK3 and IK1 is a key step and also initiates gap junction-dependent conducted dilations. We assessed the role of SK3, IK1, and connexin40 (Cx40) in muscular contraction-induced dilations in the microcirculation in vivo. Hitherto, arterioles were observed in the electrically stimulated cremaster skeletal muscle of anesthetized mice lacking SK3, IK1, or Cx40 using intravital microscopy. Genetic deficiency of SK3, but not of IK1, strongly attenuated dilations to muscular contraction. Similarly, pharmacologic blockade of SK3 by the specific blocker UCL1684 impaired such dilations in wild-type and IK1-deficient mice. In contrast, IK1 was required for acetylcholine-induced dilations. Genetic deficiency of Cx40 also attenuated dilations induced by muscular contraction but not by acetylcholine. These data support the concept that endothelial hyperpolarization through activation of SK3 contributes to exercise hyperemia and the hyperpolarization ascends the vascular tree through gap junctions formed by Cx40 to orchestrate dilation. The differential impact of SK3- and IK1-deficiency on dilations to distinct stimuli suggests stimulus-dependent activation of these endothelial channels.-Milkau, M., Kohler, R., de Wit, C. Crucial importance of the endothelial K+ channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction. FASEB J. 24, 3572-3579 (2010). www.fasebj.org