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Hydrogen Peroxide Produced by Angiopoietin-1 Mediates Angiogenesis

¹ Centre for Cell Signaling Research, Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University, Seoul, Korea; ² Biomedical Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejon, Korea; and ³ Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan

Requests for reprints: Kong-Joo Lee, Centre for Cell Signaling Research, Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea. Phone: 82-2-3277-3038; Fax: 82-2-3277-3760; E-mail: kjl{at}ewha.ac.kr.

Angiopoietin-1 (Ang1) mediates angiogenesis by enhancing endothelial cell survival and migration. It is also known that Ang1 activates Tie2, an endothelial-specific tyrosine kinase receptor, but the molecular mechanism of this process is not clear. In this study, we investigated whether reactive oxygen species (ROS) production plays a role in Ang1-mediated angiogenesis. We found that human umbilical vein endothelial cells treated with Ang1 produce ROS transiently, which was suppressed by NADPH oxidase inhibitor, diphenylene-iodonium chloride, and rotenone. The Ang1-induced ROS was identified as hydrogen peroxide (H₂O₂) using adenovirus-catalase infection. Removal of H₂O₂ by adenovirus-catalase significantly suppressed Ang1-induced in vitro endothelial cell migration, in vivo tubule formation and angiogenesis, and activation of p44/42 mitogen-activated protein kinase (MAPK), involved in cell migration, and delayed the deactivation of Akt phosphorylation involved in cell survival. Supporting to in vitro data, Ang1-induced vascular remodeling in catalase (–/–) mice was more prominent than in catalase (+/+) mice: Ang1-induced increases of the diameter of terminal arterioles and the postcapillary venules in catalase (–/–) mice were significant compared with catalase (+/+) mice. These results show that Ang1-induced H₂O₂ plays an important role in Ang1-mediated angiogenesis by modulating p44/42 MAPK activity. (Cancer Res 2006; 66(12): 6167-74)

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