Amplification of EDHF-type vasodilatations in TRPC1-deficient mice
Amplification of EDHF-type vasodilatations in TRPC1-deficient mice
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DOI：
10.1111/j.1476-5381.2010.00985.x
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发表时间：
2010-12-01
影响因子：
7.3
通讯作者：
Kohler, Ralf
中科院分区：
文献类型：
--
作者：
Schmidt, Kjestine;Dubrovska, Galyna;Kohler, Ralf
背景技术SETRPC 1通道在血管系统中表达，并且是细胞内Ca 2+处理的假定候选者。然而，关于它们在内皮依赖性血管舒张包括内皮源性超极化因子（EDHF）血管舒张中的作用知之甚少，这需要激活Ca 2+激活的K+通道（K-Ca）。为了提供TRPC 1对K-Ca功能和EDHF信号复合物作用的分子信息，我们检测了TRPC 1缺陷小鼠（TRPC 1-/-）的内皮依赖性和非依赖性血管舒张、K-Ca电流和平滑肌收缩性。我们进行了电生理测量，共聚焦钙离子成像研究K-Ca通道功能和Ca 2 + sparks.KEY TSTRPC 1在颈动脉中的缺陷产生了TRAM-34和UCL 1684敏感的EDHF型血管舒张和乙酰胆碱的内皮超极化的两倍增强。NO介导的血管舒张没有变化。TRPC 1-/-在体内表现出增强的EDHF-型血管舒张，在阻力大小的小动脉中与降低的自发张力相关。内皮IKCa/SKCa型K-Ca电流，平滑肌细胞Ca 2+火花和相关的BKCa介导的自发瞬时外向电流在TRPC 1-/-中没有变化。TRPC 1-/-组由受体操作的Ca 2+内流或Ca 2+释放诱导的平滑肌收缩力和内皮非依赖性血管舒张功能未发生改变。TRPC 1-/-表现出较低的收缩压，确定由尾袖血压measurements.CONCLUSIONS和IMPLICATIONSOUR数据表明，TRPC 1作为内皮细胞K-Ca通道依赖EDHF型血管舒张的负调节剂，从而有助于血压调节。因此，我们提出了TRPC 1在EDHF-K-Ca信号复合物中的特定作用，并建议通过增强EDHF血管舒张来药理学抑制TRPC 1可能是降低血压的新策略。
BACKGROUND AND PURPOSETRPC1 channels are expressed in the vasculature and are putative candidates for intracellular Ca2+ handling. However, little is known about their role in endothelium-dependent vasodilatations including endothelium-derived hyperpolarizing factor (EDHF) vasodilatations, which require activation of Ca2+-activated K+ channels (K-Ca). To provide molecular information on the role of TRPC1 for K-Ca function and the EDHF signalling complex, we examined endothelium-dependent and independent vasodilatations, K-Ca currents and smooth muscle contractility in TRPC1-deficient mice (TRPC1-/-).EXPERIMENTAL APPROACHVascular responses were studied using pressure/wire myography and intravital microscopy. We performed electrophysiological measurements, and confocal Ca2+ imaging for studying K-Ca channel functions and Ca2+ sparks.KEY RESULTSTRPC1 deficiency in carotid arteries produced a twofold augmentation of TRAM-34- and UCL1684-sensitive EDHF-type vasodilatations and of endothelial hyperpolarization to acetylcholine. NO-mediated vasodilatations were unchanged. TRPC1-/- exhibited enhanced EDHF-type vasodilatations in resistance-sized arterioles in vivo associated with reduced spontaneous tone. Endothelial IKCa/SKCa-type K-Ca currents, smooth muscle cell Ca2+ sparks and associated BKCa-mediated spontaneous transient outward currents were unchanged in TRPC1-/-. Smooth muscle contractility induced by receptor-operated Ca2+ influx or Ca2+ release and endothelium-independent vasodilatations were unaltered in TRPC1-/-. TRPC1-/- exhibited lower systolic blood pressure as determined by tail-cuff blood pressure measurements.CONCLUSIONS AND IMPLICATIONSOur data demonstrate that TRPC1 acts as a negative regulator of endothelial K-Ca channel-dependent EDHF-type vasodilatations and thereby contributes to blood pressure regulation. Thus, we propose a specific role of TRPC1 in the EDHF-K-Ca signalling complex and suggest that pharmacological inhibition of TRPC1, by enhancing EDHF vasodilatations, may be a novel strategy for lowering blood pressure.