1. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice.
- Author
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Yang L, Kwon J, Popov Y, Gajdos GB, Ordog T, Brekken RA, Mukhopadhyay D, Schuppan D, Bi Y, Simonetto D, and Shah VH
- Subjects
- 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, Liver pathology, Liver Cirrhosis, Experimental chemically induced, Liver Cirrhosis, Experimental genetics, Liver Cirrhosis, Experimental immunology, Liver Cirrhosis, Experimental pathology, Liver Cirrhosis, Experimental prevention & control, Macrophages immunology, Macrophages metabolism, Matrix Metalloproteinase 13 metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Monocytes immunology, Monocytes metabolism, Promoter Regions, Genetic, Receptor, Macrophage Colony-Stimulating Factor genetics, Remission Induction, Tacrolimus Binding Protein 1A genetics, Tacrolimus Binding Protein 1A metabolism, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A immunology, fas Receptor metabolism, Liver metabolism, Liver Cirrhosis, Experimental metabolism, Liver Regeneration, Vascular Endothelial Growth Factor A metabolism
- 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., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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