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Cited by 153Liver physiology and pathologyDrug-Induced Hepatotoxicity and ProtectionLiver Disease Diagnosis and Treatment

Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice

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Duan, Juan‐Li, Ruan, Bai, Yan, Xian‐Chun, Liang, Liang, Song, Ping, Yang, Zi‐Yan, Liu, Yuan, Dou, Ke‐Feng +2 more·2018·Hepatology
DOI 10.1002/hep.29834PMC PMC6099357
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Abstract

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‐specific 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‐associated genes and increased continuous EC‐associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl 4 . Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte‐supporting angiocrine profile of LSECs by down‐regulating 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‐sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis. Conclusion: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS‐sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (H epatology 2018).

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  • Notch can modulate STAT3 activity and influence dedifferentiation of liver sinusoidal endothelial cells, which is crucial for liver repair.

    “Additionally, Notch can modulate STAT3 activity and influence the dedifferentiation of LSECs (liver sinusoidal endothelial cells), which is crucial for liver repair mechanisms[58].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [58]

    The Discussion (page not provided) reports that Notch activation increases LSEC dedifferentiation and reduces signals that support hepatocyte proliferation during liver regeneration. It identifies eNOS–sGC signaling, not STAT3, as the pathway affected; the passages retrieved for STAT3 do not support that part of the claim. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Duan, J., Ruan, B., Yan, X., Liang, L., Song, P., Yang, Z., Liu, Y., Dou, K., Han, H., & Wang, L.
Affiliations
  • Department of Hepatobiliary Surgery, Xi‐Jing Hospital,Fourth Military Medical University,Xi'an,China
  • Xijing Hospital (CN)
  • State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China
  • State Key Laboratory of Cancer Biology (CN)
Corresponding author
  • Han, Hua
  • Wang, Lin
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-04-26
Volume
68
Issue
2
Pages
677-690
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.29834
PMC
PMC6099357
OpenAlex
W2789487989
Cited by
153
References
3
Citations by year
2026: 19 · 2025: 18 · 2024: 29 · 2023: 20 · 2022: 21 · 2021: 22 · 2020: 14 · 2019: 7 · 2018: 3
FWCI
7.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81770560, 31370769, 31730041, 31301194, 31671523, 81370512, 81422009, 91339115)
  • Fourth Military Medical University
  • National Key Research and Development Program of China (2015CB553702)
  • National Key Research and Development Program of China Stem Cell and Translational Research
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
Notch signaling, liver sinusoidal endothelial cells, angiocrine signaling, liver fibrosis, liver regeneration, YC-1, Wnt9b, hepatocyte growth factor, hepatocyte proliferation, CCl4-induced fibrosis, endothelial fenestrations
MeSH terms
Animals, Enzyme-Linked Immunosorbent Assay, Liver, Liver Cirrhosis, Liver Regeneration, Male, Mice, Inbred C57BL, Blotting, Western, Signal Transduction, Cell Culture Techniques, Gene Expression Profiling, Hepatocytes, Endothelial Cells, Cell Proliferation, Mice, Receptors, Notch, Real-Time Polymerase Chain Reaction

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