Vascular Endothelial Growth Factor Promotes Fibrosis Resolution and Repair in Mice

• DOI: 10.1053/j.gastro.2014.01.061
• Publication Date: 2014-02-04T14:00:23Z
• Authors: Liu Yang; Junghee Kwon; Yury Popov; Gabriella B. Gajdos; Tamas Ordog; Rolf A. Brekken; Debabrata Mukhopa...; Detlef Schuppan; Yan Bi; Douglas Simonetto; Vijay H. Shah
• Keywords: Genetic Vectors; Gene Transfer Techniques; Jejunostomy; Apoptosis; Liver Cirrhosis, Experimental; Antibodies, Neutralizing; Chemokine CXCL9; Coculture Techniques; Adenoviridae; Injections; 3. Good health; Capillary Permeability; Liver; Human Umbilical Vein Endothelial Cells; Animals; Humans; Bile Ducts; Carbon Tetrachloride; Cholecystostomy; Ligation; Cells, Cultured

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.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.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.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.