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- Title
The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells.
- Authors
Venkatraman, Lakshmi; Tucker‐Kellogg, Lisa
- Abstract
Background & Aims A fenestrated phenotype is characteristic of liver sinusoidal endothelial cells ( LSECs), but liver sinusoids become defenestrated during fibrosis and other liver diseases. Thrombospondin-1 ( TSP1) is a matrix glycoprotein with pro-fibrotic effects, and the CD47-binding fragment of TSP1 also has anti-angiogenic effects in endothelial cells. We hypothesized that the CD47-binding fragment of TSP1 could induce defenestration in LSECs through the Rho-Rho kinase ( ROCK)-myosin pathway. Methods Freshly isolated rat LSECs were treated with TSP1 or CD47-binding peptides of TSP1. LSEC fenestration was assessed with scanning electron microscopy, and myosin phosphorylation was assessed with immuno-fluorescence. Results Treating LSECs with TSP1 caused a dose-dependent loss of fenestrae, and this effect could not be blocked by SB-431542, the TGF-β1 receptor inhibitor. A CD47-binding fragment of TSP1, p4N1, was able to induce defenestration, and a CD47-blocking antibody, B6H12, was able to suppress p4N1-induced defenestration. The p4N1 fragment also caused contraction of fenestra size, correlated with an increase in myosin activation. Pretreatment with Y-237642 (a ROCK inhibitor) prevented p4N1-induced myosin activation and fenestrae decrease. Simvastatin has also been shown to antagonize Rho- ROCK signalling, and we found that simvastatin pretreatment protected LSECs from p4N1-induced myosin activation and defenestration. Conclusions We conclude that CD47 signals through the Rho- ROCK-myosin pathway to induce defenestration in LSECs. In addition, our results show that simvastatin and Y-237642 have a beneficial impact on fenestration in vitro, providing an additional explanation for the efficacy of these compounds for regression of liver fibrosis.
- Subjects
CD47 antigen; PEPTIDES; THROMBOSPONDIN-1; ENDOTHELIAL cells; LIVER cells; FIBROSIS
- Publication
Liver International, 2013, Vol 33, Issue 9, p1386
- ISSN
1478-3223
- Publication type
Article
- DOI
10.1111/liv.12231