{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:33:26Z","timestamp":1793406806465,"version":"4.5.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild-type C57BL\/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (<jats:italic>Vcam1<jats:sup>\u0394end<\/jats:sup><\/jats:italic>) and control mice (<jats:italic>Vcam1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic>) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from <jats:italic>Vcam1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> or <jats:italic>Vcam1<jats:sup>\u0394end<\/jats:sup><\/jats:italic> and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a \u03bc-Slide 2 well co-culture system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in <jats:italic>Vcam1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice and restored in <jats:italic>Vcam1<jats:sup>\u0394end<\/jats:sup><\/jats:italic> mice in both NASH and liver fibrosis models. Co-immunostaining showed increased \u03b1-smooth muscle actin in the livers of <jats:italic>Vcam1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the <jats:italic>Vcam1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice but not <jats:italic>Vcam1<jats:sup>\u0394end<\/jats:sup><\/jats:italic> mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed <jats:italic>Vcam1<jats:sup>\u0394end<\/jats:sup><\/jats:italic> mice compared to <jats:italic>Vcam1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs <jats:italic>in vitro<\/jats:italic>, supporting the profibrogenic role of LSEC VCAM1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.983255","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T08:58:25Z","timestamp":1661417905000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":76,"title":["Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver 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