title: Arsenic increases Pi-mediated vascular calcification and induces premature senescence in vascular smooth muscle cells.
abstract: Several mechanisms have been proposed to explain the vascular toxicity of arsenic. Some of them are described in this work, such as stress-induced premature senescence (SIPS), dedifferentiation, and medial vascular calcification, and they all affect vascular smooth muscle cells (VSMC). Rat aortic VSMC were treated with 1-100 µM of either sodium arsenate (As(V)), sodium arsenite (As(III)), monomethylarsonic acid, or dimethylarsinic acid. None of the treatments induced VSMC calcification in the presence of 1mM inorganic phosphate (Pi), but 1 µM As(III) did increase calcification when induced with 2.5mM Pi. A lactate dehydrogenase assay revealed that this increase was explained by a rise in cytotoxicity due to simultaneous incubation with 1 µM As(III) and 2.5mM Pi. This calcification increase was also observed in the aortas of a vascular calcification model: 5/6 nephrectomized rats fed with a high Pi diet and treated with vitamin D(3). Several known mechanisms that might explain arsenic toxicity in our experimental model were discarded: apoptosis, oxidative stress, and inflammasome activation. Nevertheless, both senescence-associated β-galactosidase activity and p21 expression were increased by As(III), which reveals the induction of SIPS. As(III) also caused dedifferentiation of VSMC, as shown by the reduced expression of the VSMC markers SM22α and calponin. Senescence and gene expression were also observed in the aortas of healthy rats treated with 50 ppm As(V) in drinking water for 1 month. In conclusion, both premature senescence in aortic VSMC with phenotypic dedifferentiation and the increase of Pi-induced calcification are novel mechanisms of arsenic vasculotoxicity.
authors.affiliation: Department of Toxicology, University of Zaragoza,  Zaragoza, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martín-Pardillos
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sosa
authors.forename: Victor
authors.initials: V
authors.lastname: Sorribas
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D002114:Calcinosis; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004357:Drug Synergism; D020287:In Situ Nick-End Labeling; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D010710:Phosphates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010710:Phosphates; D001151:Arsenic