TRPV1 expressed throughout the arterial circulation regulates vasoconstriction and blood pressure.
TRPV1 expressed throughout the arterial circulation regulates vasoconstriction and blood pressure.
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TRPV1在整个动脉循环中表达，调节血管收缩和血压。
DOI：
10.1113/jp279909
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Ahern GP
中科院分区：
文献类型：
--
作者：
Phan TX;Ton HT;Gulyás H;Pórszász R;Tóth A;Russo R;Kay MW;Sahibzada N;Ahern GP
辣椒素受体TRPV 1是参与炎症疼痛信号传导的关键离子通道。虽然主要在感觉神经中进行研究，但有报道称TRPV 1在血管系统的孤立节段中表达，但该通道是否定位于血管内皮或平滑肌仍存在争议，TRPV 1在动脉中的分布和功能作用仍不清楚。我们绘制了整个小鼠动脉循环的功能性TRPV 1表达。结合Ca 2+成像的报告小鼠系TRPV 1 PLAP-nlacZ和TRPV 1-Cre：tdTomato的分析显示TRPV 1特异性定位于心脏中的末端小动脉的平滑肌、脂肪组织和骨骼肌。辣椒素诱发内向电流（感觉神经元的电流密度约为10%），并升高动脉平滑肌细胞的细胞内Ca 2+水平，收缩离体和体内小动脉，并增加小鼠和大鼠的全身血压。此外，辣椒素显着和剂量依赖性减少冠状动脉流量。TRPV 1的药理学和/或遗传破坏消除了辣椒素的所有这些作用以及由溶血磷脂酸（一种由血小板和致动脉粥样硬化斑块产生的生物活性脂质）引发的血管收缩。值得注意的是，感觉神经的消融并不影响辣椒素的反应，揭示了血管平滑肌限制的信号传导机制。此外，与感觉神经不同，TRPV 1在动脉中的功能对活动诱导的脱敏有抵抗力。因此，血管肌细胞中的TRPV 1激活能够产生持续的去极化电流，导致冠状动脉、骨骼肌和脂肪小动脉收缩以及全身血压持续升高。
The capsaicin receptor, TRPV1, is a key ion channel involved in inflammatory pain signalling. Although mainly studied in sensory nerves, there are reports of TRPV1 expression in isolated segments of the vasculature, but whether the channel localizes to vascular endothelium or smooth muscle is controversial and the distribution and functional roles of TRPV1 in arteries remain unknown. We mapped functional TRPV1 expression throughout the mouse arterial circulation. Analysis of reporter mouse lines TRPV1PLAP-nlacZ and TRPV1-Cre:tdTomato combined with Ca2+ imaging revealed specific localization of TRPV1 to smooth muscle of terminal arterioles in the heart, adipose tissue and skeletal muscle. Capsaicin evoked inward currents (current density ~10% of sensory neurons) and raised intracellular Ca2+ levels in arterial smooth muscle cells, constricted arterioles ex vivo and in vivo and increased systemic blood pressure in mice and rats. Further, capsaicin markedly and dose-dependently reduced coronary flow. Pharmacological and/or genetic disruption of TRPV1 abolished all these effects of capsaicin as well as vasoconstriction triggered by lysophosphatidic acid, a bioactive lipid generated by platelets and atherogenic plaques. Notably, ablation of sensory nerves did not affect the responses to capsaicin revealing a vascular smooth muscle-restricted signalling mechanism. Moreover, unlike in sensory nerves, TRPV1 function in arteries was resistant to activity-induced desensitization. Thus, TRPV1 activation in vascular myocytes enables a persistent depolarizing current, leading to constriction of coronary, skeletal muscle and adipose arterioles and a sustained increase in systemic blood pressure.