title: Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Department III, University Hospital Aachen, Aachen, Germany.
authors.forename: Hacer
authors.initials: H
authors.lastname: Sahin
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.forename: Christoph
authors.initials: C
authors.lastname: Kuppe
authors.forename: Mirko Moreno
authors.initials: MM
authors.lastname: Zaldivar
authors.forename: Christoph
authors.initials: C
authors.lastname: Grouls
authors.forename: Muhammad
authors.initials: M
authors.lastname: Al-samman
authors.forename: Andreas
authors.initials: A
authors.lastname: Nellen
authors.forename: Petra
authors.initials: P
authors.lastname: Schmitz
authors.forename: Daniel
authors.initials: D
authors.lastname: Heinrichs
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Berres
authors.forename: Dennis
authors.initials: D
authors.lastname: Doleschel
authors.forename: David
authors.initials: D
authors.lastname: Scholten
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054370:Chemokine CXCL9 / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D011897:Random Allocation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D054370:Chemokine CXCL9; D007371:Interferon-gamma; D040301:Vascular Endothelial Growth Factor Receptor-2