Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver

Abstract

Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. Conclusion: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver. T he vascular effects of arsenic are a global public health concern that contribute to disease in tens of millions of people worldwide. 1 Whereas the role of environmental contaminants in the etiology of vascular diseases and in the vascular contributions to organ dysfunction remains poorly defined, epidemiological studies have associated As(III) exposures to increased risk of cardiovascular diseases 1 and vascular contributions to liver disease. 2 Liver effects associated with arsenic in drinking water include noncirrhotic portal fibrosis and, to a lesser extent, portal hypertension. 2,3 These pathologic conditions involve increased vascular channels in the portal regions of the liver. Higher levels of chronic As(III) consumption increase urinary levels of porphyrins, a biomarker for liver injury, which are more pronounced in people under 20 years of age. 4 In addition, cardiac and liver disorders are the major side effects of therapeutic As(III) regimes that treat leukemias. 5 Despite epidemiological evidence that the liver vasculature is a pathogenic target of chronic As(III) ingestion, 2 the direct effects of As(III) on liver vascular cells are unknown.In other vascular beds and isolated cell cultures, As(III) affects both endothelial and smooth muscle cell physiology. Arsenic(III) stimulates angiogenic processes in cultured endotheli...

The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization

“…Recently, Straub and colleagues 28 showed that prolonged exposure of mice to arsenic (III) initiated vascular remodeling by SEC capillarization, which was paralleled by increased sinusoidal CD31 expression, similar to our observation in HCC. 28 In this respect, our previous observation of increased numbers of alpha-smooth muscle actin-positive cells adjacent to CD34 expressing sinusoidal cells in HCC, 11 along with our current finding of increased Ang-1 in HCC, support the concept of sinusoidal remodeling in which recruitment of pericytes is stimulated by Ang-1. 29 Additionally, some tumors acquire their vasculature by vessel cooption instead of angiogenic sprouting.…”

Apo-14 is required for digestive system organogenesis during fish embryogenesis and larval development

“…4). It is well known that liver sinusoidal endothelial cells constitute unique sinusoid capillaries that differ from other capillaries in the body (Braet and Wisse, 2002;Lee et al, 2007;Straub et al, 2007), and are necessary for liver morphogenesis, even before the formation of vasculature (Matsumoto et al, 2001). The current study not only revealed predominant existence of CagApo-14 in the endothelial cells (Fig.…”

Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

“…Besides reducing the number of vessels, As 2 O 3 also influences the vascular morphology and function. Adding As 2 O 3 into the drinking water for mice induced significant vascular remodeling, with increased sinusoidal endothelial cell capillarization, resulting in decreased permeability and transport function (41). In another study, As 2 O 3 (10 mg/kg i.p.)…”