Endothelial pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure in mice

eLife

Richard D Minshall¹  Cheikh I Seye²  Soham A Shah³  Brant E Isakson⁴  Victor E Laubach⁵  Eliska Klimentova⁶  Zdravka Daneva⁶  Maniselvan Kuppusamy⁶  Yen Lin Chen⁶  Swapnil K Sonkusare⁷  Matteo Ottolini⁸ 

[1] Department of Anesthesiology, Department of Pharmacology, University of Illinois, Chicago, United States;Department of Biochemistry, University of Missouri-Columbia, Columbia, United States;Department of Biomedical Engineering, University of Virginia, Charlottesville, United States;Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States;Department of Surgery, University of Virginia, Charlottesville, United States;Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States;Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States;Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States;Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, United States;Department of Pharmacology, University of Virginia, Charlottesville, United States;

关键词: TRP channel;    Pannexin 1;    purinergic signaling;    Caveolin 1;    pulmonary vasculature;    Mouse;   

DOI  :  10.7554/eLife.67777

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY