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ToxSci Advance Access published online on January 8, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn003
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Positive signaling interactions between arsenic and ethanol for angiogenic gene induction in human microvascular endothelial cells.

Linda R. Klei and Aaron Barchowsky

Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, 15219

Corresponding author: Aaron Barchowsky, Ph.D., Department of Environmental and ccupational Health, Bridgeside Point, 100 Technology Drive, Rm 332, Pittsburgh, PA 15219, 412 624-8864, aab20{at}pitt.edu

Received October 5, 2007; revision received January 3, 2008; accepted January 3, 2008


  Abstract

Arsenic in the drinking water may promote vascular diseases in millions of people worldwide through unresolved mechanisms. In addition, little is known of the effects of co-exposures to arsenic and other common vasculature toxicants, such as alcohol. To investigate signaling interactions between arsenic and alcohols, primary human microvascular endothelial (HMVEC) cells were exposed to non-cytotoxic concentrations of arsenite (1-5 µM) in the presence or absence of 0.1% ethanol (EtOH). Co-exposure, but not exposure to either agent alone, rapidly increased active Fyn tyrosine kinase, tyrosine phosphorylation of a 109 kDa protein and serine phosphorylation of PKC{delta}. The 109 kDa protein was identified as PYK2, a regulator of vascular integrin signaling and an upstream activator of PKC{delta}. Membrane localization of PLC{gamma}1 was increased by co-exposure within 15 min, but not by not be either agent alone. In contrast, both agents equally increased membrane localization of Rac1-GTPase. Co-exposure, but not exposure to either agent alone, induced transcript levels for the angiogenic genes, vascular endothelial cell growth factor (Vegfa) and insulin-like growth factor-1 (Igf1). However, EtOH inhibited arsenic-induced, NF-{kappa}B-driven IL-8 and collagen-1 expression. Differential effects of selective PKC inhibitors on induced gene expression combined with a lack of interaction for induction of hemeoxygenase-1 further demonstrated that arsenic-responsive signaling pathways differ in sensitivity to EtOH interactions. Finally, co-exposure enhanced endothelial tube formation in in vitro angiogenesis assays. These data indicate that complex interactions occur between arsenic and EtOH exposures that functionally affect endothelial signaling for gene induction and remodeling stimuli.

Key Words: arsenic; alcohol; endothelial; angiogenesis; cell signaling.

Email address: LRK: lik10{at}pitt.edu, AB: aab20{at}pitt.edu


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[Abstract] [Full Text] [PDF]


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