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Original article
CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis
  1. Josef Ehling1,2,
  2. Matthias Bartneck3,
  3. Xiao Wei3,
  4. Felix Gremse1,
  5. Viktor Fech3,
  6. Diana Möckel1,
  7. Christer Baeck3,
  8. Kanishka Hittatiya4,
  9. Dirk Eulberg5,
  10. Tom Luedde3,
  11. Fabian Kiessling1,
  12. Christian Trautwein3,
  13. Twan Lammers1,6,7,
  14. Frank Tacke3
  1. 1Department of Experimental Molecular Imaging, Medical Faculty, Helmholtz Institute for Biomedical Engineering, RWTH University, Aachen, Germany
  2. 2Institute of Pathology, Medical Faculty, RWTH University, Aachen, Germany
  3. 3Department of Medicine III, Medical Faculty, RWTH University, Aachen, Germany
  4. 4Institute of Pathology, University Bonn, Bonn, Germany
  5. 5NOXXON Pharma AG, Berlin, Germany
  6. 6Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
  7. 7Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  1. Correspondence to Dr Frank Tacke, Department of Medicine III, Medical Faculty of the RWTH Aachen, Pauwelsstr 30, Aachen 52074, Germany; frank.tacke{at}gmx.net and Dr Twan Lammers, Department of Experimental Molecular Imaging, Medical Faculty of the RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany; tlammers{at}ukaachen.de

Abstract

Objectives In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesised that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis.

Design Angiogenesis in livers of c57BL/6 mice upon carbon tetrachloride- or bile duct ligation-induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro computed tomography (µCT) and ex vivo anatomical µCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36.

Results Contrast-enhanced in vivo µCT imaging allowed non-invasive monitoring of the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, colocalised with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including upregulated VEGF and MMP9. Functional in vivo and anatomical ex vivo µCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis.

Conclusions Inflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo µCT methodology can accurately monitor angiogenesis and antiangiogenic therapy effects in experimental liver fibrosis.

  • FIBROSIS
  • ANGIOGENESIS
  • MACROPHAGES
  • COMPUTER TOMOGRAPHY
  • CHEMOKINES

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