{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:28:44Z","timestamp":1786516124199,"version":"build-2736575974"},"reference-count":35,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,8,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Previous studies have established an association between Ninjurin2 and diseases related to vascular endothelial dysfunction, such as ischemic stroke and coronary heart disease. Given that impaired pulmonary endothelial barrier function is a critical feature of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), we hypothesized that Ninjurin2 may also participate in the regulation of lung vascular permeability. Therefore, this study investigates the role of Ninjurin2 in regulating endothelial cell function and dysfunction, aiming to elucidate the underlying mechanisms in ALI and ARDS. This study utilized both animal models and in\u00a0vitro experiments to investigate the role of Ninjurin2 in regulating endothelial cell function and dysfunction. Endothelial\u2010specific Ninjurin2 overexpressing (\n                    <jats:italic>NINJ2\u2010TG<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>EC<\/jats:italic>\n                    <\/jats:sup>\n                    ) mice were generated and compared with control mice (\n                    <jats:italic>NINJ2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>flox\/flox<\/jats:italic>\n                    <\/jats:sup>\n                    ). To assess vascular permeability across various organs, we employed Evans Blue dye extravasation assays. At the cellular level, fluorescein isothiocyanate\u2010dextran (FITC\u2010dextran) flux assays were utilized to evaluate endothelial barrier integrity. Additionally, co\u2010immunoprecipitation (Co\u2010IP) and Western blotting were performed to investigate the interaction between Ninjurin2 and VEGFR2 and to analyze the activation of the VEGF\/VEGFR2 signaling pathway.\n                    <jats:italic>NINJ2\u2010TG<\/jats:italic>\n                    <jats:sup>EC<\/jats:sup>\n                    mice developed severe lung injury with significantly increased vascular permeability in multiple organs. Overexpression of Ninjurin2 inhibited VE\u2010cadherin and ZO\u20101 expression, leading to disruption of endothelial adherens and tight junctions and increased endothelial permeability in\u00a0vivo and in\u00a0vitro. Ninjurin2 bound directly to VEGFR2 and activated VEGFR2\/AKT signaling and enhanced VEGF165\u2010induced barrier dysfunction. Pharmacological inhibition or genetic silencing of VEGFR2 reversed Ninjurin2\u2010mediated vascular leakage and pulmonary pathology. Furthermore, Ninjurin2 overexpression induced ROS accumulation, AKT\/NF\u2010\u03baB\/ICAM\u20101 activation, and monocyte\u2010endothelial adhesion. These data establish that Ninjurin2 compromises endothelial barrier integrity and promotes vascular inflammation through a VEGFR2\u2010dependent mechanism. Ninjurin2 exacerbates vascular endothelial hyperpermeability, particularly in the lungs, by interacting with VEGFR2 and activating the VEGF\/VEGFR2 signaling pathway. The results suggest that Ninjurin2 could be a useful therapeutic target for ALI and ARDS.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600727r","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T06:51:28Z","timestamp":1785480688000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ninjurin2 Promotes Pulmonary Endothelial Barrier Dysfunction Through\n                    <scp>VEGF<\/scp>\n                    \/\n                    <scp>VEGFR2<\/scp>\n                    Signaling Pathway"],"prefix":"10.1096","volume":"40","author":[{"given":"Huixin","family":"Peng","sequence":"first","affiliation":[{"name":"Shandong Provincial Lab for Clinical Immunology Translational Medicine in Universities, First Affiliated Hospital of Shandong First Medical University\/Shandong Province Qianfoshan Hospital, Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubing","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Medical Genomics, Biomedical Sciences College &amp; Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), First Affiliated Hospital of Shandong First Medical University\/Shandong Province Qianfoshan Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liujinhong","family":"Han","sequence":"additional","affiliation":[{"name":"College of Pulmonary and Critical Care Medicine, the 8th Medical Centre Chinese PLA General Hospital  Beijing P. R. 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