Purinergic P2Y2 receptor-induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR-induced activation of endothelial TRPV4 channels,...

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Published in:Science signaling 2023-10, Vol.16 (808), p.eadg1553-eadg1553
Main Authors: Kuppusamy, Maniselvan, Ta, Huy Q, Davenport, Hannah N, Bazaz, Abhishek, Kulshrestha, Astha, Daneva, Zdravka, Chen, Yen-Lin, Carrott, Philip W, Laubach, Victor E, Sonkusare, Swapnil K
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Connexins - genetics
Connexins - metabolism
Edema - metabolism
Edema - pathology
Endothelial Cells - metabolism
Humans
Inflammation - metabolism
Lung - metabolism
Mice
Nerve Tissue Proteins - metabolism
Receptors, Purinergic P2Y2 - genetics
Receptors, Purinergic P2Y2 - metabolism
Reperfusion Injury - metabolism
TRPV Cation Channels - genetics
TRPV Cation Channels - metabolism
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Summary:Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR-induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model of IRI in mice, we found that lung IRI increased the efflux of ATP through pannexin 1 (Panx1) channels at the endothelial cell (EC) membrane. Elevated extracellular ATP activated Ca influx through endothelial TRPV4 channels downstream of purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro models of IR. Endothelium-specific deletion of P2Y2R, TRPV4, or Panx1 in mice substantially prevented lung IRI-induced activation of endothelial TRPV4 channels and lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a mediator of the pathological sequelae of IRI in the lung and show that disruption of the endothelial Panx1-P2Y2R-TRPV4 signaling pathway could be a promising therapeutic strategy for preventing lung IRI after transplantation.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.adg1553