Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice
- University of Virginia, United States
- University of Illinois, United States
- University of Missouri, United States
Abstract
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 of 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 Ca (PKCa), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCa, 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.
Data availability
All data generated or analyzed during this study are included in the manuscript. Individual numeric values are shown in the scatterplots for each dataset. An excel sheet with source data for Figure 1J has been provided.
Article and author information
Author details
Swapnil K Sonkusare
Funding
National Institutes of Health (HL146914)
- Swapnil K Sonkusare
National Institutes of Health (HL142808)
- Swapnil K Sonkusare
National Institutes of Health (HL157407)
- Victor E Laubach
- Swapnil K Sonkusare
National Institutes of Health (P01HL120840)
- Brant E Isakson
National Institutes of Health (HL137112)
- Brant E Isakson
National Institutes of Health (R01HL133293)
- Victor E Laubach
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mark T Nelson, University of Vermont, United States
Ethics
Animal experimentation: All animal protocols were approved by the University of Virginia Animal Care and Use Committee (protocols 4100 and 4120). This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. For surgical procedures, every effort was made to minimize suffering.
Version history
- Received: February 22, 2021
- Preprint posted: March 9, 2021 (view preprint)
- Accepted: September 6, 2021
- Accepted Manuscript published: September 7, 2021 (version 1)
- Version of Record published: September 17, 2021 (version 2)
Copyright
© 2021, Daneva et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice
eLife 10:e67777.
https://doi.org/10.7554/eLife.67777
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