Published online before print April 6, 2009

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2009.081016v1 174/5/1949    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Straub, A. C. Articles by Barchowsky, A. Search for Related Content PubMed PubMed Citation Articles by Straub, A. C. Articles by Barchowsky, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arsenic Hazardous Substances DB ARSENIC COMPOUNDS ARSENIC, ELEMENTAL

(American Journal of Pathology. 2009;174:1949-1958.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081016

Arsenic Requires Sphingosine-1-Phosphate Type 1 Receptors to Induce Angiogenic Genes and Endothelial Cell Remodeling

Adam C. Straub^*, Linda R. Klei^*, Donna B. Stolz and Aaron Barchowsky^*

From the Departments of Environmental and Occupational Health,^* and Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania

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 (S1P₁) inhibitor VPC23019 or performing small interfering RNA knockdown of S1P₁ 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 S1P₁ 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 S1P₁ in mediating arsenic stimulation of both angiogenesis and pathogenic LSEC capillarization, as well as demonstrating a role for S1P₁ in mediating environmental responses in the liver vasculature, providing possible mechanistic insight into arsenic-induced vascular pathogenesis and disease.

This article has been cited by other articles:

				A. Lencinas, D. M. Broka, J. H. Konieczka, S. E. Klewer, P. B. Antin, T. D. Camenisch, and R. B. Runyan Arsenic Exposure Perturbs Epithelial-Mesenchymal Cell Transition and Gene Expression In a Collagen Gel Assay Toxicol. Sci., July 1, 2010; 116(1): 273 - 285. [Abstract] [Full Text] [PDF]