{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:36:22Z","timestamp":1792640182469,"version":"4.5.0"},"reference-count":47,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"808","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2023,10,24]]},"abstract":"<jats:p>\n                    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\u2013induced 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\n                    <jats:sup>2+<\/jats:sup>\n                    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\u2013induced 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.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adg1553","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T13:58:50Z","timestamp":1698155930000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":27,"title":["Purinergic P2Y2 receptor\u2013induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4579-584X","authenticated-orcid":true,"given":"Maniselvan","family":"Kuppusamy","sequence":"first","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy Q.","family":"Ta","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2385-0356","authenticated-orcid":true,"given":"Hannah N.","family":"Davenport","sequence":"additional","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Bazaz","sequence":"additional","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astha","family":"Kulshrestha","sequence":"additional","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdravka","family":"Daneva","sequence":"additional","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1149-394X","authenticated-orcid":true,"given":"Yen-Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2056-0550","authenticated-orcid":true,"given":"Philip W.","family":"Carrott","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9673-5383","authenticated-orcid":true,"given":"Victor E.","family":"Laubach","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9587-9342","authenticated-orcid":true,"given":"Swapnil K.","family":"Sonkusare","sequence":"additional","affiliation":[{"name":"Robert M.\u00a0Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA."},{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOT.0000000000000304"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1177\/1089253212458329"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(01)03606-2"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2008.03.073"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOT.0000000000000854"},{"key":"e_1_3_2_7_2","unstructured":"in TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades W.\u00a0B.\u00a0Liedtke S.\u00a0Heller Eds. 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