Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

Abstract

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 was observed in Matrigel plugs implanted in C57BL/6 mice following 5 week exposures to 5-500 ppb arsenic (Soucy et al., 2005). 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.

Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase–generated superoxide

“…Capillarization was confirmed in confocal images of sections stained with anti-PECAM-1, demonstrating a reciprocal dose-response relationship for arsenic-stimulated junctional PECAM-1 expression relative to porosity ( Figure 2A). As in previous studies (22,23), there were no signs of SEC injury or cell death, nor were there any signs of injury in surrounding stellate cells or hepatocytes.…”

“…Decreased liver metabolism of lipids, glucose, and other nutrients promotes atherogenesis after capillarization in response to several environmental stressors and aging (13,18). We previously demonstrated that arsenic stimulates SEC capillarization and remodeling of the liver vasculature (22,23). Our present results provide support for an arsenic-stimulated mechanism that requires Nox2-based oxidase-generated oxidants to defenestrate and capilliarize SECs as well as impair their physiological functions.…”

“…have demonstrated that there was no increase in inflammatory cells in the livers of mice exposed for 2 wk to the higher arsenic dose of 250 ppb (23). Since arsenic-induced defenestration is fully manifested within 2 wk, these data suggest that arsenic directly affects the SECs or surrounding cells to induce capillarization rather than a through a mechanism requiring leukocyte oxidase activity.…”

“…Animal experiments were performed in agreement with institutional guidelines for animal safety and welfare at the University of Pittsburgh. Wild-type C57BL/6 Tac mouse exposures were performed as described previously (22,23). Serial dilutions were used to prepare drinking water with sodium In C and D, significance of differences was determined by ANOVA followed by NewmanKeuls post test.…”

“…In addition, loss of lipid metabolism or removal of acylated or glycolated proteins following capillarization may enhance atherosclerosis, insulin resistance, and possibly metabolic disease (13,20,21). Recently, environmental arsenic exposures (250 ppb) were shown to promote progressive SEC capillarization in intact mice through an unresolved mechanism (22,23).…”