title: Coordinated regulation of angiopoietin-1 and vascular endothelial growth factor by arsenite in human brain microvascular pericytes: implications of arsenite-induced vascular dysfunction.
abstract: Arsenite is an environmental toxicant that is associated with vascular disease; however, the underlying mechanism of its toxicity has yet to be elucidated. Vascular stability appears to be tightly regulated by several vasoactive proteins produced by two adjacent vascular cells, endothelial cells (EC) and pericytes. The disruption of vascular stability may be involved in arsenite toxicity. The roles of angipoietins (Ang) and vascular endothelial growth factor (VEGF) in this process have been evaluated, but these studies have mostly been limited to EC. In this study, we used human brain microvascular pericytes (HBMP) to evaluate the effects of arsenite on Ang-1 and VEGF regulation. Ang-2 was reported to be not detected in HBMP. Arsenite decreased Ang-1 secretion in a time and dose-dependent manner, while it increased VEGF secretion. Although arsenite did not alter Ang-1 mRNA expression, it increased intracellular Ang-1 protein levels in a dose-dependent manner, suggesting a role for arsenite in the intracellular trapping of Ang-1. Contrary to Ang-1, the expression of VEGF mRNA was dose-dependently up-regulated by arsenite. Treatment with N-actyl-l:-cysteine (NAC) alone decreased the release of Ang-1, but failed to attenuate the arsenite-induced decrease in Ang-1 secretion, while NAC completely blocked the arsenite-stimulated VEGF secretion. These results indicate that reactive oxygen species are involved in the regulation of VEGF, but not of Ang-1, secretion in response to arsenite treatment in pericytes. Furthermore, immunocytochemical analysis using confocal microscopy revealed a colocalization of Ang-1 with actin filaments that occurred independently of tubulin. In conclusion, arsenite decreases Ang-1 secretion and increases VEGF secretion, which may offer new insight into understanding the arsenite toxicity associated with vascular instability and subsequent development of vascular disease.
authors.affiliation: Center for Biomedical Research, National Institute of Health, Seoul, South Korea.
authors.forename: Jae-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Jungwon
authors.initials: J
authors.lastname: Seo
authors.forename: Yong-Ou
authors.initials: YO
authors.lastname: Kim
authors.forename: Ho-Sa
authors.initials: HS
authors.lastname: Lee
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects*; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D020286:Pericytes / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013723:Teratogens / Q000633:toxicity*; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000199:Actins; D042683:Angiopoietin-1; D018053:Arsenites; D013723:Teratogens; D042461:Vascular Endothelial Growth Factor A; C015001:arsenite; D000111:Acetylcysteine