Vascular endothelial growth factor promotes fibrosis resolution and repair in mice.

Abstract

BACKGROUND & AIMS:

Vascular endothelial growth factor (VEGF)-induced angiogenesis is implicated in fibrogenesis and portal hypertension. However, the function of VEGF in fibrosis resolution has not been explored.

METHODS:

We developed a cholecystojejunostomy procedure to reconstruct biliary flow after bile duct ligation in C57BL/6 mice to generate a model of fibrosis resolution. These mice were then given injections of VEGF-neutralizing (mcr84) or control antibodies, and other mice received an adenovirus that expressed mouse VEGF or a control vector. The procedure was also performed on macrophage fas-induced apoptosis mice, in which macrophages can be selectively depleted. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, vascular permeability, real-time polymerase chain reaction, and flow cytometry assays.

RESULTS:

VEGF-neutralizing antibodies prevented development of fibrosis but also disrupted hepatic tissue repair and fibrosis resolution. During fibrosis resolution, VEGF inhibition impaired liver sinusoidal permeability, which was associated with reduced monocyte migration, adhesion, and infiltration of fibrotic liver. Scar-associated macrophages contributed to this process by producing the chemokine (C-X-C motif) ligand 9 (CXCL9) and matrix metalloproteinase 13. Resolution of fibrosis was impaired in macrophage fas-induced apoptosis mice but increased after overexpression of CXCL9.

CONCLUSIONS:

In a mouse model of liver fibrosis resolution, VEGF promoted fibrogenesis, but was also required for hepatic tissue repair and fibrosis resolution. We observed that VEGF regulates vascular permeability, monocyte infiltration, and scar-associated macrophages function.

• Authors: Liu Yang, Junghee Kwon, Yury Popov, Gabriella B Gajdos, Tamas Ordog, Rolf A Brekken, Debabrata Mukhopadhyay, Detlef Schuppan, Yan Bi, Douglas Simonetto, Vijay H Shah
• Journal: Gastroenterology (Gastroenterology) Vol. 146 Issue 5 Pg. 1339-50.e1 (May 2014) ISSN: 1528-0012 [Electronic] United States
• PMID: 24503129 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Neutralizing
• Chemokine CXCL9
• Cxcl9 protein, mouse
• Fas protein, mouse
• Vascular Endothelial Growth Factor A
• fas Receptor
• vascular endothelial growth factor A, mouse
• Carbon Tetrachloride
• Receptor, Macrophage Colony-Stimulating Factor
• Matrix Metalloproteinase 13
• Mmp13 protein, mouse
• Tacrolimus Binding Protein 1A

Topics

• Adenoviridae (genetics)
• Animals
• Antibodies, Neutralizing (administration & dosage)
• Apoptosis
• Bile Ducts (surgery)
• Capillary Permeability
• Carbon Tetrachloride
• Cells, Cultured
• Chemokine CXCL9 (metabolism)
• Cholecystostomy
• Coculture Techniques
• Gene Transfer Techniques
• Genetic Vectors
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Injections
• Jejunostomy
• Ligation
• Liver (immunology, metabolism, pathology)
• Liver Cirrhosis, Experimental (chemically induced, genetics, immunology, metabolism, pathology, prevention & control)
• Liver Regeneration
• Macrophages (immunology, metabolism)
• Matrix Metalloproteinase 13 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monocytes (immunology, metabolism)
• Promoter Regions, Genetic
• Receptor, Macrophage Colony-Stimulating Factor (genetics)
• Remission Induction
• Tacrolimus Binding Protein 1A (genetics, metabolism)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics, immunology, metabolism)
• fas Receptor (metabolism)