Low concentrations of arsenic induce vascular endothelial growth factor and nitric oxide release and stimulate angiogenesis in vitro.
Arsenic (As) is widely distributed in nature, and its contamination in drinking water remains a major public health problem. Exposure to As may lead to degenerative peripheral vascular diseases. The purpose of this study is to clarify the role of As in modulating cell proliferation and in vitro angiogenesis in human umbilical vein endothelial cells (HUVECs) and to scrutinize the contributing factors of these events. The results revealed that lower concentrations (up to 1 microM) of sodium arsenite stimulated HUVEC cell growth. An in vitro angiogenesis assay indicated that low concentrations of As increased vascular tubular formation, which was abrogated by hemoglobin, a potent nitric oxide scavenger. In contrast, higher concentrations of As (>5 micro M) revealed cytotoxicity and inhibition to angiogenesis. We also demonstrated that lower concentrations of As upregulated the expression of constitutive nitric oxide synthase (NOS3) at both transcriptional and translational levels and that lower concentrations of As implicated a modulatory role in vascular endothelial growth factor (VEGF) expression. In addition, low concentrations of As (<1 micro M) increased von Willebrand Factor (vWF) antigen expression, whose elevation paralleled the onset of angiogenesis and was considered an early indicator of endothelial activation in tumor metastasis. VEGF and basic fibroblast growth factor can synergistically upregulate the vWF gene expression. Therefore, we conclude that the treatment of HUVECs with As leads to cell proliferation and activation, which preferentially enhances angiogenesis in vitro, possibly via the VEGF-NOS signaling pathway. The molecular mechanism(s) by which As facilitates angiogenesis remains to be elucidated.
Kao
Ying-Hsien
YH
Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. dermyu@ha.mc.ntu.edu.tw
Yu
Chia-Li
CL
Chang
Louis W
LW
Yu
Hsin-Su
HS
D018053:Arsenites / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005434:Flow Cytometry; D006801:Humans; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D018053:Arsenites; D004785:Environmental Pollutants; D017670:Sodium Compounds; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C017947:sodium arsenite