Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension.
Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension.
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DOI：
10.1161/hypertensionaha.117.09757
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Hill MA
中科院分区：
文献类型：
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作者：
Hong K;Li M;Nourian Z;Meininger GA;Hill MA
研究表明，小动脉压力诱导的血管收缩可由G蛋白偶联受体启动，包括血管紧张素II型1受体（AT1R）。这就提出了一个问题，这些机制是否受到负反馈的调节？目前的研究检查了当机械应力或血管紧张素II （Ang II）激活时，血管平滑肌细胞（VSMCs）中g蛋白信号蛋白（RGS）的调节因子是否与AT1R共定位，以及这是否调节AT1R介导的血管收缩。为了确定AT1R的激活是否会招募RGS5，在没有或存在坎地沙坦（一种AT1R阻阻剂）的情况下，用Ang II或低渗溶液处理的cremaster肌小动脉VSMCs的原代培养物中进行了原位邻近结扎试验（PLA）。PLA结果显示RGS5向活化的AT1R的转运/易位呈浓度依赖性增加，坎地沙坦可减弱这种转运/易位。在完整的小动脉中，RGS5的下调增强了对Ang II的收缩，增强了对腔内压力增加的肌源性反应。坎地沙坦在RGS5 sirna转染的小动脉中更大程度地减弱了肌原性收缩，这与RGS5参与下调at1r介导的信号传导一致。此外，自发性高血压大鼠（SHR） VSMCs中RGS5的易位受损。这与rgs5介导的AT1R信号失调可能导致高血压患者血管过度收缩一致。在完整的血管中，与对照组相比，坎地沙坦在更大程度上减少了SHR患者的肌源性血管收缩。总的来说，这些发现表明，AT1R激活导致RGS5向质膜易位，通过其在Gq/11蛋白依赖信号传导中的作用，限制了AT1R介导的血管收缩。
Studies suggest that arteriolar pressure-induced vasoconstriction can be initiated by G protein-coupled receptors, including the angiotensin II type 1 receptor (AT1R). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether regulators of G-protein signaling proteins (RGS) in vascular smooth muscle cells (VSMCs) are co-localized with the AT1R when activated by mechanical stress or angiotensin II (Ang II) and if this modulates AT1R-mediated vasoconstriction. To determine if activation of the AT1R recruits RGS5, an in situ proximity ligation assay (PLA) was performed in primary cultures of cremaster muscle arteriolar VSMCs treated with Ang II or hypotonic solution in the absence or presence of candesartan (an AT1R blocker). PLA results revealed a concentration-dependent increase in trafficking/translocation of RGS5 towards the activated AT1R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to Ang II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to down regulation of AT1R-mediated signaling. Further, translocation of RGS5 was impaired in VSMCs of spontaneously hypertensive rats (SHR). This is consistent with dysregulated (RGS5-mediated) AT1R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in SHR compared to controls. Collectively, these findings suggest that AT1R activation results in translocation of RGS5 towards the plasma membrane, limiting AT1R-mediated vasoconstriction through its role in Gq/11 protein-dependent signaling.