Endothelial pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice.
Endothelial pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice.
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DOI：
10.7554/elife.67777
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发表时间：
2021-09-07
期刊：
影响因子：
7.7
通讯作者：
Sonkusare SK
中科院分区：
文献类型：
--
作者：
Daneva Z;Ottolini M;Chen YL;Klimentova E;Kuppusamy M;Shah SA;Minshall RD;Seye CI;Laubach VE;Isakson BE;Sonkusare SK
Pannexin 1 (Panx1) 是一种 ATP 流出途径，与肺毛细血管炎症有关。然而，内皮 Panx1 在肺血管系统中的生理作用尚不清楚。内皮瞬时受体电位香草酸 4 (TRPV4) 通道下肺动脉 (PA) 收缩力，外源 ATP 激活内皮 TRPV4 通道。我们假设内皮 Panx1-ATP-TRPV4 通道信号传导促进血管舒张并降低肺动脉压 (PAP)。 Panx1 的敲除增加了内皮细胞（而非平滑肌）的 PA 收缩性，并提高了小鼠的 PAP。流动/剪切应力增加了 PA 中通过内皮 Panx1 的 ATP 流出。 Panx1 流出的细胞外 ATP 通过嘌呤能 P2Y2 受体 (P2Y2R) 发出信号，激活蛋白激酶 Cα (PKCα)，进而激活内皮 TRPV4 通道。最后，caveolin-1 为 PA 中的内皮 Panx1、P2Y2R、PKCα 和 TRPV4 通道提供信号支架，促进它们的空间邻近性并实现信号相互作用。这些结果表明，由 Caveolin-1 促进的内皮 Panx1-P2Y2R-TRPV4 通道信号传导可降低小鼠 PA 收缩性并降低 PAP。
Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.