Article (Scientific journals)
Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice
Moreno Zaldivar, Mirko; Sahin, Hacer; Borkham-Kamphorst, Erawan et al.
2012In Hepatology, 55 (5), p. 1610-1619
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Keywords :
alpha smooth muscle actin; angiogenesis inhibitor; antifibrotic agent; carbon tetrachloride; chemokine receptor CXCR3; CXCL11 chemokine; CXCL9 chemokine; gamma interferon; animal cell; antiangiogenic activity; antifibrotic activity; neovascularization (pathology); Cell Movement; Chemokine CXCL9; Inbred C57BL
Abstract :
[en] Recent data suggest that the chemokine receptor CXCR3 is functionally involved in fibroproliferative disorders, including liver fibrosis. Neoangiogenesis is an important pathophysiological feature of liver scarring, but a functional role of angiostatic CXCR3 chemokines in this process is unclear. We therefore investigated neoangiogenesis in carbon tetrachloride (CCl 4)-induced liver fibrosis in Cxcr3 -/- and wildtype mice by histological, molecular, and functional imaging methods. Furthermore, we assessed the direct role of vascular endothelial growth factor (VEGF) overexpression on liver angiogenesis and the fibroproliferative response using a Tet-inducible bitransgenic mouse model. The feasibility of attenuation of angiogenesis and associated liver fibrosis by therapeutic treatment with the angiostatic chemokine Cxcl9 was systematically analyzed in vitro and in vivo. The results demonstrate that fibrosis progression in Cxcr3 -/- mice was strongly linked to enhanced neoangiogenesis and VEGF/VEGFR2 expression compared with wildtype littermates. Systemic VEGF overexpression led to a fibrogenic response within the liver and was associated with a significantly increased Cxcl9 expression. In vitro, Cxcl9 displayed strong antiproliferative and antimigratory effects on VEGF-stimulated endothelial cells and stellate cells by way of reduced VEGFR2 (KDR), phospholipase Cγ (PLCγ), and extracellular signal-regulated kinase (ERK) phosphorylation, identifying this chemokine as a direct counter-regulatory molecule of VEGF signaling within the liver. Accordingly, systemic administration of Cxcl9 led to a strong attenuation of neoangiogenesis and experimental liver fibrosis in vivo. Conclusion: The results identify direct angiostatic and antifibrotic effects of the Cxcr3 ligand Cxcl9 in a model of experimental liver fibrosis. The amelioration of liver damage by systemic application of Cxcl9 might offer a novel therapeutic approach for chronic liver diseases associated with increased neoangiogenesis. © 2011 American Association for the Study of Liver Diseases.
Disciplines :
Genetics & genetic processes
Author, co-author :
Moreno Zaldivar, Mirko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Sahin, Hacer
Borkham-Kamphorst, Erawan
Kuppe, Christoph
Grouls, Christoph
Al-samman, Muhammad
Nellen, Andreas
Schmitz, Petra
Heinrichs, Daniel
Berres, Marie-Luise
Doleschel, Dennis
Scholten, David
Weiskirchen, Ralf
Moeller, Marcus J.
Kiessling, Fabian
Trautwein, Christian
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Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice
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Peer reviewed
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