Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice.
The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.
Straub
Adam C
AC
Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, PA 15219, USA.
Stolz
Donna B
DB
Vin
Harina
H
Ross
Mark A
MA
Soucy
Nicole V
NV
Klei
Linda R
LR
Barchowsky
Aaron
A
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008871:Microvilli / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011042:Poisons / Q000633:toxicity*; D011509:Proteoglycans
D004338:Drug Combinations; D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011042:Poisons; D011509:Proteoglycans; C121346:laminin 1; C059485:matrigel; D003094:Collagen; D001151:Arsenic