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      Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice

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          To investigate the effect of carvedilol on liver fibrosis and hepatic sinusoidal capillarization in mice with carbon tetrachloride (CCl 4)-induced fibrosis.


          A liver fibrosis mouse model was induced by intraperitoneal CCl 4 injection for 8 weeks. The mice were divided into five experimental groups: the normal group, the oil group, the CCl 4 group, the CCl 4+carvedilol (5 mg/kg/d) group, and the CCl 4+carvedilol (10 mg/kg/d) group. The extent of liver fibrosis was evaluated by histopathological staining, and the changes in fenestrations of hepatic sinus endothelial cells were observed by scanning electron microscope (SEM). The expression of α-smooth muscle actin (α-SMA) and vascular endothelial markers was detected by immunohistochemistry and Western blot assays. The effect of carvedilol on cell apoptosis was studied via Terminal deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL) assay, and the serum levels of matrix metalloproteinase-8 (MMP-8), vascular endothelial growth factor (VEGF), and angiopoietin-2 were detected through a Luminex assay.


          Liver fibrosis in CCl 4-treated mice was attenuated by reduced accumulation of collagen and the reaction of inflammation with carvedilol treatment. Carvedilol reduced the activation of hepatic stellate cells (HSCs) and increased the number of apoptotic cells. The expression of α-SMA, CD31, CD34 and VWF (von Willebrand factor) was significantly decreased after carvedilol treatment. In addition, the number of fenestrae in the hepatic sinusoid showed notable differences between the groups, and the serum levels of MMP-8, VEGF and angiopoietin-2 were increased in the mice with liver fibrosis and reduced by carvedilol treatment.


          The study demonstrated that carvedilol could prevent further development of liver fibrosis and hepatic sinusoidal capillarization in mice with CCl 4-induced fibrosis.

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          Most cited references 40

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          Liver sinusoidal endothelial cells in hepatic fibrosis.

           Laurie DeLeve (2015)
          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.
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            The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity.

            A look through the literature on liver sinusoidal endothelial cells (LSECs) reveals that there are several conflicts among different authors of what this cell type is and does. Major controversies that will be highlighted in this review include aspects of the physiological role, the characterization, and the protocols of isolation and cultivation of these cells. Many of these conflicts may be ascribed to the fact that the cell was only recently established as a distinct cell type and that researchers from different disciplines tend to define their structure and function differently. This field is in need of a common platform to obtain a sound communication and a unified understanding of how to interpret novel research results. The aim of this review is to encourage scientists not to ignore the fact that there are, indeed, different opinions in the literature on LSECs. We also hope that this review will point out to the reader that some issues that may seem well established regarding our knowledge about the LSECs, in reality, are still unresolved and, indeed, controversial.
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              Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation.

              The phenotypic features of liver sinusoidal endothelial cells (SEC), open fenestrae in sieve plates and lack of a basement membrane, are lost with capillarization. The current study examines localization of CD31 as a marker for the dedifferentiated, nonfenestrated SEC and examines regulation of SEC phenotype in vitro. CD31 localization in SEC was examined by confocal microscopy and immunogold-scanning electron microscopy. SEC cultured for 1 day express CD31 in the cytoplasm, whereas after 3 days, CD31 is also expressed on cell-cell junctions. Immunogold-scanning electron microscopy confirmed the absence of CD31 surface expression on fenestrated SEC 1 day after isolation and demonstrated the appearance of CD31 surface expression on SEC that had lost fenestration after 3 days in culture. SEC isolated from fibrotic liver do show increased expression of CD31 on the cell surface. Coculture with either hepatocytes or stellate cells prevents CD31 surface expression, and this effect does not require heterotypic contact. The paracrine effect of hepatocytes or stellate cells on SEC phenotype is abolished with anti-VEGF antibody and is reproduced by addition of VEGF to SEC cultured alone. VEGF stimulates SEC production of nitric oxide. NG-nitro-L-arginine methyl ester blocked the paracrine effect of hepatocytes or stellate cells on SEC phenotype and blocked the ability of VEGF to preserve the phenotype of SEC cultured alone. In conclusion, surface expression of CD31 is a marker of a dedifferentiated, nonfenestrated SEC. The VEGF-mediated paracrine effect of hepatocytes or stellate cells on maintenance of SEC phenotype requires autocrine production of nitric oxide by SEC.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                01 August 2019
                : 13
                : 2667-2676
                [1 ] Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province, People’s Republic of China
                [2 ] Department of Health Digestion, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province, People’s Republic of China
                Author notes
                Correspondence: Chun-Qing ZhangDepartment of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University , 324 Jingwu Weiqi Road, Jinan250021, Shandong Province, People’s Republic of ChinaTel +86 5 316 877 3293Fax +86 5 318 790 6348 Email zhangchunqing_sdu@ 123456163.com
                © 2019 Wu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 46, Pages: 10
                Original Research


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