Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure.
Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure.
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DOI：
10.1161/atvbaha.118.311290
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发表时间：
2018-09
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影响因子：
--
通讯作者：
Isakson BE
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文献类型：
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作者：
DeLalio LJ;Keller AS;Chen J;Boyce AKJ;Artamonov MV;Askew-Page HR;Keller TCS 4th;Johnstone SR;Weaver RB;Good ME;Murphy SA;Best AK;Mintz EL;Penuela S;Greenwood IA;Machado RF;Somlyo AV;Swayne LA;Minshall RD;Isakson BE
交感神经支配的血管平滑肌细胞（VSMCs）是一个主要的调节小动脉血管收缩，血管阻力，血压（BP）。重要的是，α-肾上腺素能受体刺激，其独特地与Pannexin 1（Panx 1）通道介导的ATP释放通道在阻力动脉中偶联，也需要定位于膜小窝。在这里，我们测试，如果本地化的Panx 1小窝蛋白-1促进通道功能（刺激依赖性ATP释放和肾上腺素能血管收缩），是重要的血压稳态。我们使用体外VSMC培养模型，离体阻力动脉，和一种新的诱导型VSMC特异性小窝蛋白-1敲除小鼠来探测Panx 1和小窝蛋白-1之间的相互作用。我们报告说，Panx 1和小窝蛋白-1共定位于血管平滑肌细胞质膜上的阻力动脉交感神经附近的肾上腺素能刺激依赖性的方式。Caveolin-1基因缺失显著减弱肾上腺素能刺激的ATP释放和血管收缩，对内皮依赖性血管舒张或心脏功能没有直接影响。在VSMC小窝蛋白-1缺乏的小鼠中发生平均动脉压的显著降低（总计= 4 mmHg;夜间= 7 mmHg）。这些动物对使用Panx 1肽抑制剂PxIL 2 P1进一步降低血压具有抗性，该抑制剂靶向通道功能所必需的细胞内环区域。在VSMCs中，Panx 1向小窝蛋白-1富集的小窝的易位增强了适当的肾上腺素能介导的血管收缩和BP稳态所必需的嘌呤能刺激的释放。
Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure (BP). Importantly, α-adrenergic receptor stimulation, which uniquely couples with Pannexin 1 (Panx1) channel-mediated ATP release channels in resistance arteries, also requires localization to membrane caveolae. Here we test if localization of Panx1 to caveolin-1 promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for BP homeostasis. We use in vitro VSMC culture models, ex vivo resistance arteries, and a novel inducible VSMC-specific caveolin-1 knockout mouse to probe interactions between Panx1 and caveolin-1. We report that Panx1 and caveolin-1 co-localized on the VSMC plasma membrane of resistance arteries near sympathetic nerves in an adrenergic stimulus-dependent manner. Genetic deletion of caveolin-1 significantly blunts adrenergic stimulated ATP release and vasoconstriction, with no direct influence on endothelium-dependent vasodilation or cardiac function. A significant reduction in mean arterial pressure (Total= 4 mmHg; Night= 7 mmHg) occurred in mice deficient for VSMC caveolin-1. These animals were resistant to further BP lowering using a Panx1 peptide inhibitor PxIL2P1, which targets an intracellular loop region necessary for channel function. Translocalization of Panx1 to caveolin-1-enriched caveolae in VSMCs augments the release of purinergic stimuli necessary for proper adrenergic-mediated vasoconstriction and BP homeostasis.