Defective Cx40 Maintains Cx37 Expression but Intact Cx40 Is Crucial for Conducted Dilations Irrespective of Hypertension
Defective Cx40 Maintains Cx37 Expression but Intact Cx40 Is Crucial for Conducted Dilations Irrespective of Hypertension
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DOI：
10.1161/hypertensionaha.112.201194
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发表时间：
2012-12-01
期刊：
影响因子：
8.3
通讯作者：
de Wit, Cor
中科院分区：
文献类型：
--
作者：
Jobs, Alexander;Schmidt, Kjestine;de Wit, Cor
差距连接通道蛋白连接蛋白40（Cx40）在血管和肾脏生理学中是至关重要的，因为Cx40缺陷小鼠表现出内皮依赖性扩张的传导受损和显著的高血压。后者排除了对内皮细胞Cx40作用的机械见解，因为长期高血压本身可能影响传导和Cx表达。我们的目的是确定内皮细胞Cx40功能，其依赖于传导能力，并将其与高血压相关的改变分开。我们评估了Cx40细胞类型特异性缺失的小鼠和表达人类缺陷型Cx40（Cx40 A96 S）的小鼠的传导和Cx表达，Cx40形成非传导性间隙连接通道。限制性小动脉刺激乙酰胆碱或缓激肽引起的局部扩张，进行上游的距离不衰减的幅度高达1.2毫米的控制与一个floxed Cx40基因（Cx40（fl/fl））。在高血压动物中，在肾素产生细胞中缺乏Cx40的传导反应没有改变，但在内皮细胞中缺乏Cx40的正常血压动物中，远端扩张减少（Cx40（fl/fl）：Tie 2-Cre）。令人惊讶的是，Cx 37的表达是不可检测的免疫染色的小动脉内皮细胞只有在Cx40（fl/fl）：Tie 2-Cre，然而，Cx 37的转录活性在提睾肌与Cx40（fl/fl）的控制。Cx40 A96 S小鼠高血压，Cx40和Cx 37的表达保留。然而，引导的反应是迟钝的。我们的结论是，内皮细胞Cx40是必要的，以支持内皮激动剂启动的进行扩张，并将Cx 37定位到质膜。这些功能不会因长期高血压而改变。在存在非传导性Cx40的情况下，Cx 37存在，但不能支持传导，这突出了内皮Cx40的重要性。（高血压。2012;60：1422-1429）。
The gap junction channel protein connexin40 (Cx40) is crucial in vascular and renal physiology, because Cx40-deficient mice exhibit impaired conduction of endothelium-dependent dilations and pronounced hypertension. The latter precludes mechanistic insights into the role of endothelial Cx40, because long-lasting hypertension itself may affect conduction and Cx expression. We aimed to identify endothelial Cx40 functions, their dependency on the conductive capability, and to separate these from hypertension-related alterations. We assessed conduction and Cx expression in mice with cell type-specific deletion of Cx40 and in mice expressing a defective Cx40 (Cx40A96S) identified in humans, which forms nonconducting gap junction channels. Confined arteriolar stimulation with acetylcholine or bradykinin elicited local dilations that conducted upstream without attenuation of the amplitude for distances up to 1.2-mm in controls with a floxed Cx40 gene (Cx40(fl/fl)). Conducted responses in hypertensive animals devoid of Cx40 in renin-producing cells were unaltered but remote dilations were reduced in normotensive animals deficient for Cx40 in endothelial cells (Cx40(fl/fl):Tie2-Cre). Surprisingly, Cx37 expression was undetectable by immunostaining in arteriolar endothelium only in Cx40(fl/fl):Tie2-Cre; however, transcriptional activity of Cx37 in the cremaster was comparable with Cx40(fl/fl) controls. Cx40A96S mice were hypertensive with preserved expression of Cx40 and Cx37. Nevertheless, conducted responses were blunted. We conclude that endothelial Cx40 is necessary to support conducted dilations initiated by endothelial agonists and to locate Cx37 into the plasma membrane. These functions are unaltered by long-lasting hypertension. In the presence of a nonconducting Cx40, Cx37 is present but cannot support the conduction highlighting the importance of endothelial Cx40. (Hypertension. 2012;60:1422-1429.)