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Am J Pathol. 2009 May;174(5):1949-58. doi: 10.2353/ajpath.2009.081016. Epub 2009 Apr 6.

Arsenic requires sphingosine-1-phosphate type 1 receptors to induce angiogenic genes and endothelial cell remodeling.

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Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.


Arsenic in drinking water is a major public health concern as it increases risk and incidence of cardiovascular disease and cancer. Arsenic exposure affects multiple vascular beds, promoting liver sinusoidal capillarization and portal hypertension, ischemic heart disease, peripheral vascular disease, and tumor angiogenesis. While Rac1-GTPase and NADPH oxidase activities are essential for arsenic-stimulated endothelial cell signaling for angiogenesis or liver sinusoid capillarization, the mechanism for initiating these effects is unknown. We found that arsenic-stimulated cell signaling and angiogenic gene expression in human microvascular endothelial cells were Pertussis toxin sensitive, indicating a G-protein coupled signaling pathway. Incubating human microvascular endothelial cells with the sphingosine-1-phosphate type 1 receptor (S1P(1)) inhibitor VPC23019 or performing small interfering RNA knockdown of S1P(1) blocked arsenic-stimulated HMVEC angiogenic gene expression and tube formation, but did not affect induction of either HMOX1 or IL8. Liver sinusoidal endothelial cells (LSECs) defenestrate and capillarize in response to aging and environmental oxidant stresses. We found that S1P(1) was enriched on LSECs in vivo and in primary cell culture and that VPC23019 inhibited both sphingosine-1-phosphate-stimulated and arsenic-stimulated LSEC oxidant generation and defenestration. These studies identified novel roles for S1P(1) in mediating arsenic stimulation of both angiogenesis and pathogenic LSEC capillarization, as well as demonstrating a role for S1P(1) in mediating environmental responses in the liver vasculature, providing possible mechanistic insight into arsenic-induced vascular pathogenesis and disease.

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