Low Concentrations of Arsenic Induce Vascular Endothelial Growth Factor and Nitric Oxide Release and Stimulate Angiogenesis In Vitro
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- 作者：Ying-Hsien Kao ; Chia-Li Yu ; Louis W. Chang ; and Hsin-Su Yu
- 刊名：Chemical Research in Toxicology
- 出版年：2003
- 出版时间：April 2003
- 年：2003
- 卷：16
- 期：4
- 页码：460 - 468
- 全文大小：186K
- 年卷期：v.16,no.4(April 2003)
- ISSN：1520-5010
文摘
Arsenic (As) is widely distributed in nature, and its contamination in drinking water remainsa major public health problem. Exposure to As may lead to degenerative peripheral vasculardiseases. The purpose of this study is to clarify the role of As in modulating cell proliferationand in vitro angiogenesis in human umbilical vein endothelial cells (HUVECs) and to scrutinizethe contributing factors of these events. The results revealed that lower concentrations (up to1 
M) of sodium arsenite stimulated HUVEC cell growth. An in vitro angiogenesis assayindicated that low concentrations of As increased vascular tubular formation, which wasabrogated by hemoglobin, a potent nitric oxide scavenger. In contrast, higher concentrationsof As (>5 M) revealed cytotoxicity and inhibition to angiogenesis. We also demonstrated thatlower concentrations of As upregulated the expression of constitutive nitric oxide synthase(NOS3) at both transcriptional and translational levels and that lower concentrations of Asimplicated a modulatory role in vascular endothelial growth factor (VEGF) expression. Inaddition, low concentrations of As (<1 M) increased von Willebrand Factor (vWF) antigenexpression, whose elevation paralleled the onset of angiogenesis and was considered an earlyindicator of endothelial activation in tumor metastasis. VEGF and basic fibroblast growth factorcan synergistically upregulate the vWF gene expression. Therefore, we conclude that thetreatment of HUVECs with As leads to cell proliferation and activation, which preferentiallyenhances angiogenesis in vitro, possibly via the VEGF-NOS signaling pathway. The molecularmechanism(s) by which As facilitates angiogenesis remains to be elucidated.
M) of sodium arsenite stimulated HUVEC cell growth. An in vitro angiogenesis assayindicated that low concentrations of As increased vascular tubular formation, which wasabrogated by hemoglobin, a potent nitric oxide scavenger. In contrast, higher concentrationsof As (>5 M) revealed cytotoxicity and inhibition to angiogenesis. We also demonstrated thatlower concentrations of As upregulated the expression of constitutive nitric oxide synthase(NOS3) at both transcriptional and translational levels and that lower concentrations of Asimplicated a modulatory role in vascular endothelial growth factor (VEGF) expression. Inaddition, low concentrations of As (<1 M) increased von Willebrand Factor (vWF) antigenexpression, whose elevation paralleled the onset of angiogenesis and was considered an earlyindicator of endothelial activation in tumor metastasis. VEGF and basic fibroblast growth factorcan synergistically upregulate the vWF gene expression. Therefore, we conclude that thetreatment of HUVECs with As leads to cell proliferation and activation, which preferentiallyenhances angiogenesis in vitro, possibly via the VEGF-NOS signaling pathway. The molecularmechanism(s) by which As facilitates angiogenesis remains to be elucidated.