ToxSci Advance Access published online on October 18, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm263
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The Vascular System as a Target of Metal Toxicity
* Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL 60515
Department of Environmental Health and the Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056
Department of Microbiology and Immunology, Midwestern University, 555 31st Street, Downers Grove, IL 60515
¶ Department of Occupational and Environmental Health, University of Pittsburgh Graduate School of Public Heath, Pittsburgh, PA 15219 48824
Department of Pharmacology and Toxicology, B331 Life Sciences Building, Michigan State University, East Lansing, MI
1 To whom correspondence should be addressed. Fax +44(0)16305156295. Email: wprozi{at}midwestern.edu.
Received August 23, 2007; revision received October 5, 2007; accepted October 16, 2007
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Abstract |
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Vascular system function involves complex interactions among the vascular endothelium, smooth muscle, the immune system and the nervous system. The toxic metals cadmium (Cd), arsenic (As) and lead (Pb) can target the vascular system in a variety of ways, ranging from hemorrhagic injury to subtle pathogenic remodeling and metabolic changes. Acute Cd exposure results in hemorrhagic injury to the testis, although some strains of animals are resistant to this effect. A comparison of Cd-sensitive with Cd-resistant mouse strains showed that expression of the Slc39a8 gene, encoding the ZIP8 transporter, in the testis vasculature endothelium is responsible for this difference. Endogenously, ZIP8 is a Mn2+/HCO3–symporter that may also contribute to Cd damage in the kidney. Chronic Cd exposure is associated with various cardiovascular disorders such as hypertension and cardiomyopathy and it is reported to have both carcinogenic and anti-carcinogenic activities. At non-cytotoxic concentrations of 10-100 nM, Cd can inhibit chemotaxis and tube formation of vascular endothelial cells. These angiostatic effects may be mediated through disruption of VE-cadherin, a Ca2+-dependent cell adhesion molecule. With regard to As, ingestion of water containing disease-promoting concentrations of As promotes capillarization of the liver sinusoidal endothelium. Since capillarization is a hallmark precursor for liver fibrosis and contributes to an imbalance of lipid metabolism, this As effect on hepatic endothelial cells may be a pathogenic mechanism underlying As-related vascular diseases. With regard to Pb, perinatal exposure may cause sustained elevations in adult blood pressure, and genetically susceptible animals may show enhanced sensitivity to this effect. Taken together, these data indicate that the vascular system is a critical target of metal toxicity and that actions of metals on the vascular system may play important roles in mediating the pathophysiologic effects of metals in specific target organs.
Key Words: arsenic; cadmium; lead; vasculature; endothelium; metal transporters.