title: Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide.
abstract: Environmental arsenic exposure, through drinking contaminated water, is a significant risk factor for developing vascular diseases and is associated with liver portal hypertension, vascular shunting, and portal fibrosis through unknown mechanisms. We found that the addition of low doses of arsenite to the drinking water of mice resulted in marked pathologic remodeling in liver sinusoidal endothelial cells (SECs), including SEC defenestration, capillarization, increased junctional PECAM-1 expression, protein nitration, and decreased liver clearance of modified albumin. Furthermore, the pathologic changes observed after in vivo exposure were recapitulated in isolated mouse SECs exposed to arsenic in culture. To investigate the role of NADPH oxidase-generated ROS in this remodeling, we examined the effect of arsenite in the drinking water of mice deficient for the p47 subunit of the NADPH oxidase and found that knockout mice were protected from arsenite-induced capillarization and protein nitration. Furthermore, ex vivo arsenic exposure increased SEC superoxide generation, and this effect was inhibited by addition of a Nox2 inhibitor and quenched by the cell-permeant superoxide scavenger. In addition, inhibiting either oxidant generation or Rac1-GTPase blocked ex vivo arsenic-stimulated SEC differentiation and dysfunction. Our data indicate that a Nox2-based oxidase is required for SEC capillarization and that it may play a central role in vessel remodeling following environmentally relevant arsenic exposures.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Straub
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Clark
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ross
authors.forename: Ashwin G
authors.initials: AG
authors.lastname: Chandra
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pagano
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Aaron
authors.initials: A
authors.lastname: Barchowsky
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006975:Hypertension, Portal / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C484602:Rac1 protein, mouse; D014874:Water Pollutants, Chemical; D013481:Superoxides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D001151:Arsenic