Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States.
Department of Pharmacology, University of Virginia, Charlottesville, United States.
Elife. 2021 Sep 7;10:e67777. doi: 10.7554/eLife.67777.
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.
缝隙连接蛋白 1（Panx1）是一种 ATP 外排途径，与肺毛细血管炎症有关。然而，内皮细胞 Panx1 在肺血管中的生理作用尚不清楚。内皮细胞瞬时受体电位香草醛 4（TRPV4）通道降低肺动脉（PA）收缩性，外源性 ATP 激活内皮细胞 TRPV4 通道。我们假设内皮细胞 Panx1-ATP-TRPV4 通道信号转导促进血管舒张并降低肺动脉压（PAP）。内皮细胞而非平滑肌细胞 Panx1 基因敲除增加 PA 收缩性并升高小鼠 PAP。血流/切应力增加了内皮细胞 Panx1 在 PA 中的 ATP 外排。Panx1 外排的细胞外 ATP 通过嘌呤能 P2Y2 受体（P2Y2R）信号转导激活蛋白激酶 Cα（PKCα），进而激活内皮细胞 TRPV4 通道。最后， caveolin-1 为 PA 中的内皮细胞 Panx1、P2Y2R、PKCα 和 TRPV4 通道提供了信号支架，促进它们的空间接近并实现信号相互作用。这些结果表明，内皮细胞 Panx1-P2Y2R-TRPV4 通道信号转导，由 caveolin-1 介导，可降低小鼠 PA 收缩性并降低 PAP。
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