{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T09:23:02Z","timestamp":1791969782007,"version":"4.3.4"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2018,4,26]],"date-time":"2018-04-26T00:00:00Z","timestamp":1524700800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:p>\n                    Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC\u2010specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC\u2010associated genes and increased continuous EC\u2010associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl\n                    <jats:sub>4<\/jats:sub>\n                    . Notch activation attenuated endothelial nitric oxide synthase (eNOS)\/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3\u2010(5\u2032\u2010hydroxymethyl\u20102\u2032\u2010furyl)\u20101\u2010benzylindazole (YC\u20101) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte\u2010supporting angiocrine profile of LSECs by down\u2010regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS\u2010sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS\u2010sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2018).\n                  <\/jats:p>","DOI":"10.1002\/hep.29834","type":"journal-article","created":{"date-parts":[[2018,2,8]],"date-time":"2018-02-08T16:12:41Z","timestamp":1518106361000},"page":"677-690","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":145,"title":["Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice"],"prefix":"10.1097","volume":"68","author":[{"given":"Juan\u2010Li","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xi\u2010Jing Hospital,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bai","family":"Ruan","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xi\u2010Jing Hospital,Fourth Military Medical University,Xi'an,China"},{"name":"Department of Clinical Aerospace Medicine, School of Aerospace Medicine,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian\u2010Chun","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xi\u2010Jing Hospital,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke\u2010Feng","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xi\u2010Jing Hospital,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary 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