Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure

Daneva, Z.; Ottolini, M.; Chen, Y. L.; Klimentova, E.; Shah, S. A.; Minshall, R. D.; Seye, C. I.; Laubach, V. E.; Isakson, B. E.; Sonkusare, S. K.

doi:10.1101/2021.03.09.434532

bioRxiv · 10.1101/2021.03.09.434532

Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure

Daneva, Z.·Ottolini, M.·Chen, Y. L.·Klimentova, E.·Shah, S. A.·Minshall, R. D.·Seye, C. I.·Laubach, V. E.·Isakson, B. E.·Sonkusare, S. K.

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Abstract

Pannexin 1 (Panx1) is an ATP-efflux channel that controls endothelial function in the systemic circulation. However, the roles of endothelial Panx1 in resistance-sized pulmonary arteries (PAs) are unknown. Extracellular ATP dilates PAs through activation of endothelial TRPV4 (transient receptor potential vanilloid 4) ion 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 or TRPV4 increased PA contractility and raised PAP. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase C (PKC), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKC, 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.

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Daneva, Z., Ottolini, M., Chen, Y. L., Klimentova, E., Shah, S. A., Minshall, R. D., Seye, C. I., Laubach, V. E., Isakson, B. E., Sonkusare, S. K.. 2021-03-09. Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure. https://doi.org/10.1101/2021.03.09.434532

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