Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK
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Ying Ying1,2, Takashi Ueta3, Shanshan Jiang1,2, Hui Lin1,2,, Yuanyuan Wang2, Demetrios Vavvas3, Rong Wen4, Ye-Guang Chen5 and Zhijun Luo1,2,6
1Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathology, Schools of Basic Medical Sciences and Pharmaceutical Sciences, Nanchang University Medical College, Nanchang, China
2Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
3Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
4Bascom Palmer Eye Institute, University of Miami Miller Medical School, Miami, FL, USA
5Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China
6Windsor University School of Medicine, Brighton’s Estate, Cayon, St. Kitts
Keywords: AMPK, ALK1, tumor angiogenesis
Received: December 28, 2016 Accepted: February 12, 2017 Published: March 02, 2017
Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.
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