CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis

Josef Ehling, Matthias Bartneck, Xiao Wei, Felix Gremse, Viktor Fech, Diana Möckel, Christer Baeck, Kanishka Hittatiya, Dirk Eulberg, Tom Luedde, Fabian Kiessling, Christian Trautwein, Twan Gerardus Gertudis Maria Lammers, Frank Tacke

Research output: Contribution to journalArticleAcademicpeer-review

105 Citations (Scopus)

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.
Original languageUndefined
Pages (from-to)1960-1971
JournalGut
Volume63
Issue number12
DOIs
Publication statusPublished - 2014

Keywords

  • METIS-309479
  • IR-95149

Cite this

Ehling, J., Bartneck, M., Wei, X., Gremse, F., Fech, V., Möckel, D., ... Tacke, F. (2014). CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut, 63(12), 1960-1971. https://doi.org/10.1136/gutjnl-2013-306294
Ehling, Josef ; Bartneck, Matthias ; Wei, Xiao ; Gremse, Felix ; Fech, Viktor ; Möckel, Diana ; Baeck, Christer ; Hittatiya, Kanishka ; Eulberg, Dirk ; Luedde, Tom ; Kiessling, Fabian ; Trautwein, Christian ; Lammers, Twan Gerardus Gertudis Maria ; Tacke, Frank. / CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. In: Gut. 2014 ; Vol. 63, No. 12. pp. 1960-1971.
@article{6e480064d2d6491cb81812658545026b,
title = "CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis",
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 = "METIS-309479, IR-95149",
author = "Josef Ehling and Matthias Bartneck and Xiao Wei and Felix Gremse and Viktor Fech and Diana M{\"o}ckel and Christer Baeck and Kanishka Hittatiya and Dirk Eulberg and Tom Luedde and Fabian Kiessling and Christian Trautwein and Lammers, {Twan Gerardus Gertudis Maria} and Frank Tacke",
year = "2014",
doi = "10.1136/gutjnl-2013-306294",
language = "Undefined",
volume = "63",
pages = "1960--1971",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "12",

}

Ehling, J, Bartneck, M, Wei, X, Gremse, F, Fech, V, Möckel, D, Baeck, C, Hittatiya, K, Eulberg, D, Luedde, T, Kiessling, F, Trautwein, C, Lammers, TGGM & Tacke, F 2014, 'CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis' Gut, vol. 63, no. 12, pp. 1960-1971. https://doi.org/10.1136/gutjnl-2013-306294

CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. / Ehling, Josef; Bartneck, Matthias; Wei, Xiao; Gremse, Felix; Fech, Viktor; Möckel, Diana; Baeck, Christer; Hittatiya, Kanishka; Eulberg, Dirk; Luedde, Tom; Kiessling, Fabian; Trautwein, Christian; Lammers, Twan Gerardus Gertudis Maria; Tacke, Frank.

In: Gut, Vol. 63, No. 12, 2014, p. 1960-1971.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis

AU - Ehling, Josef

AU - Bartneck, Matthias

AU - Wei, Xiao

AU - Gremse, Felix

AU - Fech, Viktor

AU - Möckel, Diana

AU - Baeck, Christer

AU - Hittatiya, Kanishka

AU - Eulberg, Dirk

AU - Luedde, Tom

AU - Kiessling, Fabian

AU - Trautwein, Christian

AU - Lammers, Twan Gerardus Gertudis Maria

AU - Tacke, Frank

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - METIS-309479

KW - IR-95149

U2 - 10.1136/gutjnl-2013-306294

DO - 10.1136/gutjnl-2013-306294

M3 - Article

VL - 63

SP - 1960

EP - 1971

JO - Gut

JF - Gut

SN - 0017-5749

IS - 12

ER -

Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Möckel D et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut. 2014;63(12):1960-1971. https://doi.org/10.1136/gutjnl-2013-306294