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In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated\u00a09 (NEDD9) and induces expression of a prothrombotic NEDD9 peptide (N9<jats:sub>P<\/jats:sub>) on the extracellular plasma membrane surface. We hypothesized that the SARS\u2010CoV\u20102\u2013ARDS pathophenotype involves increased pulmonary endothelial N9<jats:sub>P<\/jats:sub>. Paraffin\u2010embedded autopsy lung specimens were acquired from patients with SARS\u2010CoV\u20102\u2013\u200b\u200b\u200b\u200b\u200b\u200bARDS (<jats:italic>n<\/jats:italic>\u2009=\u200913), ARDS from other causes (<jats:italic>n<\/jats:italic>\u2009=\u200910), and organ donor controls (<jats:italic>n<\/jats:italic>\u2009=\u20095). Immunofluorescence characterized the expression of N9<jats:sub>P<\/jats:sub>, fibrin, and transcription factor 12\u00a0(TCF12), a putative binding target of SARS\u2010CoV\u20102 and known transcriptional regulator of <jats:italic>NEDD9<\/jats:italic>. We performed RNA\u2010sequencing on normal HPAECs treated with normoxia or hypoxia (0.2% O<jats:sub>2<\/jats:sub>) for 24\u2009h. Immunoprecipitation\u2010liquid chromatography\u2010mass spectrometry (IP\u2010LC\u2010MS) profiled protein\u2013protein interactions involving N9<jats:sub>P<\/jats:sub> relevant to thrombus stabilization. Hypoxia increased TCF12 messenger RNA significantly compared to normoxia in HPAECs in vitro (+1.19\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.001; false discovery rate\u2009=\u20090.005), and pulmonary endothelial TCF12 expression was increased threefold in SARS\u2010CoV\u20102\u2013ARDS versus donor control lungs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Compared to donor controls, pulmonary endothelial N9<jats:sub>P<\/jats:sub>\u2010fibrin colocalization was increased in situ in non\u2010SARS\u2010CoV\u20102\u2013ARDS\u00a0and SARS\u2010CoV\u20102\u2013ARDS decedents (3.7\u2009\u00b1\u20091.2 vs. 10.3\u2009\u00b1\u20093.2 and 21.8\u2009\u00b1\u20094.0\u2009arb. units, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). However, total pulmonary endothelial N9<jats:sub>P<\/jats:sub> was increased significantly only in SARS\u2010CoV\u20102\u2013ARDS versus donor controls (15\u2009\u00b1\u20094.2 vs. 6.3\u2009\u00b1\u20090.9\u2009arb. units, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). In HPAEC plasma membrane isolates, IP\u2010LC\u2010MS identified a novel protein\u2013protein interaction between NEDD9 and the \u03b2<jats:sub>3<\/jats:sub>\u2010subunit of the\u00a0\u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub>\u2010integrin, which regulates fibrin anchoring to endothelial cells. In conclusion, lethal SARS\u2010CoV\u20102\u2013ARDS is associated with increased pulmonary endothelial N9<jats:sub>P<\/jats:sub> expression and N9<jats:sub>P<\/jats:sub>\u2010fibrin colocalization in situ. Further investigation is needed to determine the pathogenetic and potential therapeutic relevance of N9<jats:sub>P<\/jats:sub> to the thrombotic pathophenotype of SARS\u2010CoV\u20102\u2013ARDS.<\/jats:p>","DOI":"10.1002\/pul2.12071","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T15:43:53Z","timestamp":1649087033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS\u2010CoV\u20102 infection"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6876-7836","authenticated-orcid":false,"given":"George A.","family":"Alba","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy O.","family":"Samokhin","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui\u2010Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley M.","family":"Wertheim","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen J.","family":"Haley","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Padera","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara O.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Pathology Boston Children's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan O.","family":"Rosas","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lida P.","family":"Hariri","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts USA"},{"name":"Department of Pathology Massachusetts General Hospital Boston 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