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Gut. 2014 Dec;63(12):1960-1971. doi: 10.1136/gutjnl-2013-306294. Epub 2014 Feb 21.

CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis.

Author information

1
Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, Medical Faculty, RWTH University, Aachen, Germany.
2
Institute of Pathology, Medical Faculty, RWTH University, Aachen, Germany.
3
Department of Medicine III, Medical Faculty, RWTH University, Aachen, Germany.
4
Institute of Pathology, University Bonn, Bonn, Germany.
5
NOXXON Pharma AG, Berlin, Germany.
6
Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
7
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
#
Contributed equally

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.

KEYWORDS:

ANGIOGENESIS; CHEMOKINES; COMPUTER TOMOGRAPHY; FIBROSIS; MACROPHAGES

PMID:
24561613
PMCID:
PMC4216733
DOI:
10.1136/gutjnl-2013-306294
[Indexed for MEDLINE]
Free PMC Article

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