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increases pulmonary vascular permeability by activation of the PGE<jats:sub>2<\/jats:sub>receptor 3 (EP<jats:sub>3<\/jats:sub>), which may explain adverse pulmonary effects of the EP<jats:sub>1<\/jats:sub>\/EP<jats:sub>3<\/jats:sub>receptor agonist sulprostone in patients. In addition, PGE<jats:sub>2<\/jats:sub>contributes to pulmonary oedema in response to platelet-activating factor (PAF). PAF increases endothelial permeability by recruiting the cation channel transient receptor potential canonical 6 (TRPC6) to endothelial caveolae<jats:italic>via<\/jats:italic>acid sphingomyelinase (ASMase). Yet, the roles of PGE<jats:sub>2<\/jats:sub>and EP<jats:sub>3<\/jats:sub>in this pathway are unknown. We hypothesised that EP<jats:sub>3<\/jats:sub>receptor activation may increase pulmonary vascular permeability by activation of TRPC6, and thus, synergise with ASMase-mediated TRPC6 recruitment in PAF-induced lung oedema.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In isolated lungs, we measured increases in endothelial calcium (\u0394Ca<jats:sup>2+<\/jats:sup>) or lung weight (\u0394weight), and endothelial caveolar TRPC6 abundance as well as phosphorylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PAF-induced \u0394Ca<jats:sup>2+<\/jats:sup>and \u0394weight were attenuated in EP<jats:sub>3<\/jats:sub>-deficient mice. Sulprostone replicated PAF-induced \u0394Ca<jats:sup>2+<\/jats:sup>and \u0394weight which were blocked by pharmacological\/genetic inhibition of TRPC6, ASMase or Src-family kinases (SrcFK). PAF, but not sulprostone, increased TRPC6 abundance in endothelial caveolae. Immunoprecipitation revealed PAF- and sulprostone-induced tyrosine-phosphorylation of TRPC6 that was prevented by inhibition of phospholipase C (PLC) or SrcFK. PLC inhibition also blocked sulprostone-induced \u0394Ca<jats:sup>2+<\/jats:sup>and \u0394weight, as did inhibition of SrcFK or inhibitory G-protein (G<jats:sub>i<\/jats:sub>) signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>EP<jats:sub>3<\/jats:sub>activation triggers pulmonary oedema<jats:italic>via<\/jats:italic>G<jats:sub>i<\/jats:sub>-dependent activation of PLC and subsequent SrcFK-dependent tyrosine phosphorylation of TRPC6. In PAF-induced lung oedema, this TRPC6 activation coincides with ASMase-dependent caveolar recruitment of TRPC6, resulting in rapid endothelial Ca<jats:sup>2+<\/jats:sup>influx and barrier failure.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.02635-2021","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T16:25:24Z","timestamp":1650558324000},"page":"2102635","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Stimulation of the EP<sub>3<\/sub>receptor causes lung oedema by activation of TRPC6 in pulmonary endothelial 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