Stretch–Activation of Angiotensin II Type 1a Receptors Contributes to the Myogenic Response of Mouse Mesenteric and Renal Arteries
Stretch–Activation of Angiotensin II Type 1a Receptors Contributes to the Myogenic Response of Mouse Mesenteric and Renal Arteries
复制标题
DOI：
10.1161/circresaha.115.302882
复制
发表时间：
2014-07
影响因子：
20.1
通讯作者：
J. Schleifenbaum;M. Kassmann;I. Szijártó;H. Hercule;J. Tano;S. Weinert;Matthias Heidenreich;A. Pathan;Yoland‐Marie Anistan;N. Alenina;N. Rusch;M. Bader;T. Jentsch;M. Gollasch
中科院分区：
文献类型：
--
作者：
J. Schleifenbaum;M. Kassmann;I. Szijártó;H. Hercule;J. Tano;S. Weinert;Matthias Heidenreich;A. Pathan;Yoland‐Marie Anistan;N. Alenina;N. Rusch;M. Bader;T. Jentsch;M. Gollasch
原理：血管壁拉伸是小动脉对压力产生肌源性反应的主要刺激。分子机制是难以捉摸的，但最近的研究结果表明，G蛋白偶联受体可以引起拉伸反应。目的：研究血管平滑肌细胞中血管紧张素II型1受体（angiotensin II type 1 receptor, AT1R）是否具有机械敏感性，并鉴定肌源性血管收缩的下游离子通道介质。方法和结果：我们使用了AT1R信号分子和推测的离子通道靶点缺乏的小鼠，即AT1R、血管紧张素原、瞬时受体电位通道6 （TRPC6）通道或电压门控K+ (Kv7)基因家族（KCNQ3、4或5）的几种亚型。我们在分离的肠系膜动脉和肾循环中发现了一种机械传感机制，该机制依赖于AT1R亚型a与Gq/11蛋白的偶联，作为完成肌源性反应的关键事件。动脉机械激活发生在AT1R药物阻断和血管紧张素原或TRPC6通道缺失的情况下。通过渗透诱导的膜拉伸激活AT1R亚型a可抑制膜片夹紧血管平滑肌细胞中XE991敏感的Kv通道电流，相似浓度的XE991可增强肠系膜和肾肌张力。虽然xe991敏感的KCNQ3、4和5通道在血管平滑肌细胞中表达，但在这些通道缺乏的动脉中，xe991敏感的K+电流和肌源性收缩持续存在。结论：我们的研究结果提供了明确的证据，表明小鼠肠系膜和肾动脉的肌生成反应依赖于AT1R亚型a的配体非依赖性机械激活。AT1R亚型a信号依赖于不同于TRPC6或KCNQ3、4或5的离子通道，以实现血管平滑肌细胞激活和血管阻力升高。
Rationale: Vascular wall stretch is the major stimulus for the myogenic response of small arteries to pressure. The molecular mechanisms are elusive, but recent findings suggest that G protein–coupled receptors can elicit a stretch response. Objective: To determine whether angiotensin II type 1 receptors (AT1R) in vascular smooth muscle cells exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction. Methods and Results: We used mice deficient in AT1R signaling molecules and putative ion channel targets, namely AT1R, angiotensinogen, transient receptor potential channel 6 (TRPC6) channels, or several subtypes of the voltage-gated K+ (Kv7) gene family (KCNQ3, 4, or 5). We identified a mechanosensing mechanism in isolated mesenteric arteries and in the renal circulation that relies on coupling of the AT1R subtype a to a Gq/11 protein as a critical event to accomplish the myogenic response. Arterial mechanoactivation occurs after pharmacological block of AT1R and in the absence of angiotensinogen or TRPC6 channels. Activation of AT1R subtype a by osmotically induced membrane stretch suppresses an XE991-sensitive Kv channel current in patch-clamped vascular smooth muscle cells, and similar concentrations of XE991 enhance mesenteric and renal myogenic tone. Although XE991-sensitive KCNQ3, 4, and 5 channels are expressed in vascular smooth muscle cells, XE991-sensitive K+ current and myogenic contractions persist in arteries deficient in these channels. Conclusions: Our results provide definitive evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand-independent, mechanoactivation of AT1R subtype a. The AT1R subtype a signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4, or 5 to enact vascular smooth muscle cell activation and elevated vascular resistance.