BACKGROUND Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ETBR (endothelin receptor type B). METHODS/RESULTS To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells. Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ETBR. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ETBR antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ETBR. Binding sites for ETBR were mapped to MasR (amino acids 290-314). Binding sites for MasR on ETBR were identified (amino acids 176-200). Peptides that disrupt MasR:ETBR prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ETBR interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses. CONCLUSIONS We identify cross talk between Ang-(1-7) and ET-1 through MasR:ETBR interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ETBR-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ETBR signaling may have therapeutic potential in conditions associated with vascular damage.

中文翻译：

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Ang-（1-7） 和 ET-1 通过 Mas 和 ETB 受体相互作用定义了一种新的血管保护机制。


背景 Ang-（1-7）（血管紧张素 （1-7）） 通过 MasR（Mas 受体）对抗 Ang II（血管紧张素 II）的血管损伤作用，如肺动脉高压模型所示。其潜在机制尚不清楚。我们假设 Ang-（1-7） 和 ET-1 （内皮素-1） 系统的保护臂之间涉及 MasR 和 ETBR （B 型内皮素受体）。方法/结果为了解决这个问题，我们研究了多个模型：体内，在 ET-1 相关血管损伤（缺氧诱导的肺动脉高压）的小鼠模型中;离体，在离体小鼠动脉中;在体外，在人内皮细胞中。肺动脉高压小鼠表现出肺血管重塑、内皮功能障碍和 ET-1 诱导的过度收缩。Ang-（1-7） 治疗 （14 天） 改善了这些作用并增加了血管 ETBR 的表达。在人内皮细胞中，A779 （MasR 拮抗剂） 和 BQ788 （ETBR 拮抗剂） 减弱了 Ang-（1-7） 诱导的 eNOS （内皮 NO 合酶）/NO 的激活。A779 抑制 ET-1 诱导的信号传导。免疫共沉淀和肽阵列实验证明了 MasR 和 ETBR 之间的相互作用。ETBR 的结合位点定位到 MasR （氨基酸 290-314）。确定了 MasR 在 ETBR 上的结合位点 （氨基酸 176-200）。破坏 MasR：ETBR 的肽阻止了 Ang-（1-7） 和 ET-1 信号转导。使用高通量筛选，我们鉴定了增强 MasR：ETBR 相互作用的化合物，我们称之为增强子。增强子增加了 Ang-（1-7） 诱导的 eNOS 活性、NO 产生和 Ang-（1-7） 介导的血管舒张，并减少了收缩反应。结论 我们通过 MasR：ETBR 相互作用将 Ang-（1-7） 和 ET-1 之间的串扰确定为一种具有血管保护性的新型网络。 促进这些系统之间的协同活性可放大 Ang-（1-7） 信号传导，增加 ET-1/ETBR 介导的血管作用，并减弱 ET-1 的有害作用。增强 Ang-（1-7）/MasR：ET-1/ETBR 信号转导在与血管损伤相关的情况下可能具有治疗潜力。