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Liver sinusoidal endothelial cells in hepatic fibrosis
Open accessAbstract
Capillarization, lack of liver sinusoidal endothelial cell (LSEC) fenestration, and formation of an organized basement membrane not only precedes fibrosis, but is also permissive for hepatic stellate cell activation and fibrosis. Thus, dysregulation of the LSEC phenotype is a critical step in the fibrotic process. Both a vascular endothelial growth factor (VEGF)‐stimulated, nitric oxide (NO)‐independent pathway and a VEGF‐stimulated NO‐dependent pathway are necessary to maintain the differentiated LSEC phenotype. The NO‐dependent pathway is impaired in capillarization and activation of this pathway downstream from NO restores LSEC differentiation in vivo . Restoration of LSEC differentiation in vivo promotes HSC quiescence, enhances regression of fibrosis, and prevents progression of cirrhosis. (H epatology 2015;61:1740–1746)
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“In healthy livers, LSECs prevent HSC activation [304].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [304]
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“Capillarized LSECs (Fig. 4), characterized by high nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent collagen IV release [305], lose their HSC-suppressive properties and thereby contribute to an environment that favors HSC activation and fibrosis [304].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [304]
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Liver Fibrosis, Liver Cancer, and Advances in Therapeutic Approaches
Rajapaksha, I. G. (2022) · Livers · doi:10.3390/livers2040028 · Cited by 14
Kaden, T., Noerenberg, A., Boldt, J., Sagawe, C., Johannssen, T., Rennert, K., Raasch, M., & Evenburg, T. (2022) · Toxicology · doi:10.1016/j.tox.2022.153374 · Cited by 13
The Effect of Splenectomy on the Reversal of Cirrhosis: a Prospective Study
Zeng, D., Liang, D., Zhang, R.-C., Guo, Q., Duan, B., Jia, C., Chen, F., Lin, D., Zang, Y., & Lu, S. (2019) · Gastroenterology Research and Practice · doi:10.1155/2019/5459427 · Cited by 12
“The elevated serum HA level in the cirrhosis patient is due to the fact that the liver sinusoidal endothelial cells reduce the uptake of HA [31].”
BackgroundAutoimmune Hepatitis and Stellate Cells: An Insight into the Role of Autophagy
Golbabapour, S., Lankarani, K. B., Ghavami, S., & Geramizadeh, B. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190402120231 · Cited by 13
Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver
Buniatian, G. H., Weiskirchen, R., Weiß, T. S., Schwinghammer, U., Fritz, M., Seferyan, T., Proksch, B., Glaser, M., Lourhmati, A., Buadze, M., et al. (2020) · Cells · doi:10.3390/cells9020452 · Cited by 13
Anatomy and Cellular Functions of the Liver
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The Liver Sinusoidal Endothelial Cell
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Wang, L., Huang, Y., Chen, J., Gao, J., Chen, S., Zhao, M., Lin, J., Zhou, S., Shen, Y., & Cheng, Y. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1635763 · Cited by 15
“During fibrosis, VEGF derived from hepatocytes and HSCs maintains the fenestration phenotype of LSECs through the eNOS-sGC pathway and non-NO-dependent pathways (DeLeve, 2015).”
Jones, A. K., Chen, H., Ng, K. J., Villalona, J., McHugh, M., Zeveleva, S., Wilks, J., Brilisauer, K., Bretschneider, T., Qian, H. S., et al. (2023) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.122.001532 · Cited by 14
“…in NO also cause capillarization of liver sinusoidal endothelial cells (LSECs), which may further promote activation of HSCs (Xie et al., 2012; DeLeve, 2015), enabling the constriction of portal blood fl ow and tissue remodeling that lead to portal hypertension and liver fi brosis (Thimgan and…”
BackgroundTan, P. K., Ostertag, T. M., Rosenthal, S. B., Chilin-Fuentes, D., Aidnik, H., Linker, S. B., Murphy, K., Miner, J. N., & Brenner, D. A. (2023) · American Journal Of Pathology · doi:10.1016/j.ajpath.2023.12.005 · Cited by 12
Advances in Noninvasive Molecular Imaging Probes for Liver Fibrosis Diagnosis
Chen, S., Zhuang, D., Jia, Q., Guo, B., & Hu, G. (2024) · Biomaterials Research · doi:10.34133/bmr.0042 · Cited by 14
“Importantly, capillarization is an early event that precedes the onset of liver fibrosis [53,54] and maybe a permissive condition for the development of fibrosis [55,56].”
BackgroundInfluence of microflow on hepatic sinusoid blood flow and red blood cell deformation
Wang, T., Lü, S., Hao, Y., Su, Z., Long, M., & Cui, Y. (2021) · Biophysical Journal · doi:10.1016/j.bpj.2021.09.020 · Cited by 12
Miao, X., Sha, T., Zhang, W., Zhou, H., Qiu, C., Deng, H., You, Y., Ren, J., Zhang, X., Zheng, R., et al. (2022) · Radiology · doi:10.1148/radiol.212325 · Cited by 12
Zheng, Y., Wang, J., Wang, J., Xie, H.-Y., & Zhao, T. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/8590638 · Cited by 12
“0is lesion can activate hepatic stellate cells, leading to liver fibrosis [29].”
BackgroundRole of Oxidative and Nitrosative Stress in Hepatic Fibrosis
le, T. T. T., Thuy, T. T. V., Hai, H., & Kawada, N. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804274-8.00016-3 · Cited by 13
Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney
Utoh, R., Komori, J., Kuge, H., Tatsumi, K., Yamada, M., Hirohashi, S., Tsutsumi, M., Amanuma, T., Yoshioka, A., Nakajima, Y., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.12.016 · Cited by 12
Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer
Sererols-Viñas, L., Garcia‐Vicién, G., Ruiz-Blázquez, P., Lee, T., Lee, Y. A., Gonzalez‐Sanchez, E., Vaquero, J., Moles, A., Filliol, A. A., & Affò, S. (2025) · Seminars in Liver Disease · doi:10.1055/a-2551-0724 · Cited by 16
Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver
Harkins, L., Vilarinho, S., & Saltzman, W. M. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00712 · Cited by 11
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“…involvement of dedi ff erentiation of LSECs in arsenic-induced hepatic stellate cell activation and liver fi brosis. observed to signi fi cantly correlate with elevated levels of α -SMA (Figure 3C) and ECM (Figure S3B) and is associated with collagen deposition and the content of Col Ⅰ (Figure 3D,E).”
BackgroundMesselmani, T., Goff, A. L., Soncin, F., Souguir, Z., Merlier, F., Maubon, N., Legallais, C., Leclerc, É., & Jellali, R. (2023) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2023.10.006 · Cited by 13
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“16,17 Dysfunctional LSECs may display pro-inflammatory phenotype, 16,18 altered production of LSEC-derived vasodilators and vasoconstrictors (e.g., NO, thromboxane A2, prostaglandins) 10,19 reduced endocytic capacity, changes in LSECs bioenergetics and other alterations in LSECs phenotype.”
BackgroundExtracellular vesicles targeting non-parenchymal cells: the therapeutical effect on liver fibrosis
Liu, Y., & Wang, L. (2024) · eGastroenterology · doi:10.1136/egastro-2023-100040 · Cited by 11
Tomala, J., Weberova, P., Tomalová, B., Zakostelska, Z. J., Sivák, L., Kovářová, J., & Kovář, M. (2021) · eLife · doi:10.7554/elife.62432 · Cited by 10
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Zhang, Q., Niu, X., Tian, L., Liu, J., Niu, R., Quan, J., Yu, J., Lin, W., Qian, Z., & Zeng, P. (2020) · Aging · doi:10.18632/aging.103234 · Cited by 11
“basement membrane and defenestration of LSECs [28, 29].”
Liu, Y., Cong, K., Li, Q., Zhang, D., & Sheng, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1741398 · Cited by 12
Metadata
- Authors
- DeLeve, L. D.
- Affiliations
- University of Southern California (US)
- Corresponding author
- DeLeve, Laurie D.
- ORCID
- DeLeve, Laurie D.
- Venue
- Hepatology
- Published
- 2015-03-23
- Volume
- 61
- Issue
- 5
- Pages
- 1740-1746
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4333127
- OpenAlex
- W1781806439
- Cited by
- 482
- References
- 50
- Citations by year
- 2026: 45 · 2025: 44 · 2024: 60 · 2023: 40 · 2022: 39 · 2021: 51 · 2020: 49 · 2019: 37 · 2018: 46 · 2017: 35 · 2016: 26 · 2015: 9
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-07-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100580, DK-66423, R01DK066423)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- liver sinusoidal endothelial cells, liver fibrosis, capillarization, endothelial fenestrations, basement membrane formation, hepatic stellate cell activation, VEGF signaling, nitric oxide, HSC quiescence, fibrosis regression, liver cirrhosis
- MeSH terms
- Cell Differentiation, Humans, Liver Cirrhosis, Endothelial Cells
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