{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:57:25Z","timestamp":1782280645719,"version":"3.54.5"},"posted":{"date-parts":[[2025,2,6]]},"group-title":"Pathology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The liver undergoes significant hemodynamic changes during surgery, transplantation, or cirrhosis with portal hypertension(PH). The hepatic artery buffer response(HABR), which compensates for reduced portal venous flow by increasing hepatic artery(HA) flow, is hypothesized to induce pathological portal tract remodeling. This study investigates the molecular mechanisms underlying this process.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>PH was induced in Sprague-Dawley rats via partial portal vein ligation(PPVL). Structural evaluation(microCT), immune cell profiling, hemodynamic measurements, and transcriptomic analysis in macrophages(M\u03d5) from sham or PPVL rats were conducted.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>MicroCT revealed decreased portal vein flow and increased HA flow correlated with portal pressure(r=0.799, p&lt;0.01). A 2-fold increase in portal tract fibrosis(p&lt;0.001) was observed with increased \u03b1-SMA+ myofibroblasts in PPVL rats. CD68+ M\u03d5 peaked at 10 days post-PPVL, and their depletion significantly reduced fibrosis(p&lt;0.001), indicating critical roles of M\u03d5 in portal tract remodeling. VCAM-1 was elevated in HA endothelium and portal fibroblasts (PFs); VCAM-1 neutralization reduced collagen accumulation(p&lt;0.05), CD68+ M\u03d5(46.3%, p&lt;0.01), and CD3+ T cells(18%, p&lt;0.05). M\u03d5-conditioned medium increased VCAM-1 in PFs(8-fold, p&lt;0.001) and enhanced PF migration, while VCAM-1 knockdown reduced this effect (p&lt;0.01). Single-cell RNA sequencing data(GSE171904) and RNA-FISH revealed increased interactions between osteopontin (Spp1)+ M\u03d5 and PFs, with Spp1+ M\u03d5 driving fibrosis. Spp1 knockdown in M\u03d5 co-culture reduced PF fibrogenic markers, while recombinant Spp1 upregulated Col1a1, Fn1, and Acta2 expression in PFs.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Increased VCAM-1 in arterial endothelial cells and PFs facilitates the recruitment of Spp1+ M\u03d5, which drive HA flow-mediated vascular remodeling and portal tract fibrosis. These findings highlight arterial flow-induced fibrosis as a key mechanism in PH, potentially contributing to disease progression and decompensation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Synopsis<\/jats:title>\n                  <jats:p>Liver hemodynamic changes in portal hypertension drive extracellular matrix accumulation and portal tract remodeling via Spp1+ macrophages. This study highlights how altered blood flow induces fibrosis, and its potential role in decompensation, and identifies therapeutic targets for advanced liver disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.31.634947","type":"posted-content","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T05:40:17Z","timestamp":1738820417000},"source":"Crossref","is-referenced-by-count":1,"title":["Hepatic Arterial Flow-Induced Portal Tract Fibrosis in Portal Hypertension: The Role of VCAM-1 and Osteopontin-Expressing Macrophages"],"prefix":"10.64898","author":[{"given":"Ruixue","family":"Ma","sequence":"first","affiliation":[{"name":"Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, 06520"},{"name":"Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, 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Connecticut, 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiewen","family":"Qi","sequence":"additional","affiliation":[{"name":"Research Center of Oral and Maxillofacial Development and Regeneration, Xiangya Hospital, Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen W.","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine & Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Yang","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Department of Internal Medicine, Yale School of 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