Nitric Oxide-Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries.
Nitric Oxide-Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries.
复制标题
一氧化氮依赖性反馈回路调节小肺动脉中的瞬态受体势触点4（TRPV4）通道合作和内皮功能。
DOI：
10.1161/jaha.117.007157
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发表时间：
2017-12-23
影响因子：
5.4
通讯作者：
Sonkusare SK
中科院分区：
文献类型：
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作者：
Marziano C;Hong K;Cope EL;Kotlikoff MI;Isakson BE;Sonkusare SK
最近的研究表明，空间受限的局部Ca 2+信号是体循环中内皮依赖性血管舒张的关键调节因子。肺动脉（PA）和体动脉之间存在巨大的功能差异，但控制PA内皮依赖性血管舒张的局部Ca 2+信号尚不清楚。通过瞬时受体电位香草酸4（TRPV 4）通道（称为TRPV 4火花）的局部单一Ca 2+内流事件通过激活Ca 2+依赖性K+通道调节阻力大小的肠系膜动脉中的内皮依赖性血管舒张。本研究的目的是确定TRPV 4 sparklets在抗性大小的PA中的独特功能作用、信号传导靶点和内源性调节剂。使用共聚焦成像、自定义图像分析和压力肌描记术在四阶PA中结合敲除小鼠模型，我们报告了一种新的Ca 2+信号传导机制，其调节阻力大小的PA中的内皮依赖性血管舒张。TRPV 4火花在PA与肠系膜动脉相比时表现出不同的空间定位，并优先激活内皮型一氧化氮合酶（eNOS）。TRPV 4-内皮一氧化氮合酶信号释放的一氧化氮不仅促进血管舒张，而且启动鸟苷酸环化酶-蛋白激酶G依赖性负反馈环，抑制TRPV 4通道的协同开放，从而限制sparklet活性。此外，我们发现三磷酸腺苷通过TRPV 4火花的P2嘌呤能受体依赖性激活来扩张PA。我们的研究结果揭示了空间上不同的TRPV 4-内皮型一氧化氮合酶信号传导机制及其在抗性大小的PA中的新型内源性调节剂。
Recent studies demonstrate that spatially restricted, local Ca2+ signals are key regulators of endothelium‐dependent vasodilation in systemic circulation. There are drastic functional differences between pulmonary arteries (PAs) and systemic arteries, but the local Ca2+ signals that control endothelium‐dependent vasodilation of PAs are not known. Localized, unitary Ca2+ influx events through transient receptor potential vanilloid 4 (TRPV4) channels, termed TRPV4 sparklets, regulate endothelium‐dependent vasodilation in resistance‐sized mesenteric arteries via activation of Ca2+‐dependent K+ channels. The objective of this study was to determine the unique functional roles, signaling targets, and endogenous regulators of TRPV4 sparklets in resistance‐sized PAs. Using confocal imaging, custom image analysis, and pressure myography in fourth‐order PAs in conjunction with knockout mouse models, we report a novel Ca2+ signaling mechanism that regulates endothelium‐dependent vasodilation in resistance‐sized PAs. TRPV4 sparklets exhibit distinct spatial localization in PAs when compared with mesenteric arteries, and preferentially activate endothelial nitric oxide synthase (eNOS). Nitric oxide released by TRPV4‐endothelial nitric oxide synthase signaling not only promotes vasodilation, but also initiates a guanylyl cyclase‐protein kinase G‐dependent negative feedback loop that inhibits cooperative openings of TRPV4 channels, thus limiting sparklet activity. Moreover, we discovered that adenosine triphosphate dilates PAs through a P2 purinergic receptor‐dependent activation of TRPV4 sparklets. Our results reveal a spatially distinct TRPV4‐endothelial nitric oxide synthase signaling mechanism and its novel endogenous regulators in resistance‐sized PAs.