Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

Ying Ying, Takashi Ueta, Shanshan Jiang, Hui Lin, Yuanyuan Wang, Demetrios Vavvas, Rong Wen, Ye Guang Chen, Zhijun Luo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 AMPKa1 and prevented by the dominant negative AMPKa1. 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.

Original languageEnglish (US)
Pages (from-to)32794-32806
Number of pages13
JournalOncotarget
Volume8
Issue number20
DOIs
StatePublished - 2017

Fingerprint

AMP-Activated Protein Kinases
Metformin
Vascular Endothelial Growth Factor A
Pathologic Neovascularization
Pharmacology
Choroidal Neovascularization
Light Coagulation
Human Umbilical Vein Endothelial Cells
Therapeutics
Endothelium
Lasers
Up-Regulation
Phosphorylation

Keywords

  • ALK1
  • AMPK
  • Tumor angiogenesis

ASJC Scopus subject areas

  • Oncology

Cite this

Ying, Y., Ueta, T., Jiang, S., Lin, H., Wang, Y., Vavvas, D., ... Luo, Z. (2017). Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. Oncotarget, 8(20), 32794-32806. https://doi.org/10.18632/oncotarget.15825

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. / Ying, Ying; Ueta, Takashi; Jiang, Shanshan; Lin, Hui; Wang, Yuanyuan; Vavvas, Demetrios; Wen, Rong; Chen, Ye Guang; Luo, Zhijun.

In: Oncotarget, Vol. 8, No. 20, 2017, p. 32794-32806.

Research output: Contribution to journalArticle

Ying, Y, Ueta, T, Jiang, S, Lin, H, Wang, Y, Vavvas, D, Wen, R, Chen, YG & Luo, Z 2017, 'Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK', Oncotarget, vol. 8, no. 20, pp. 32794-32806. https://doi.org/10.18632/oncotarget.15825
Ying Y, Ueta T, Jiang S, Lin H, Wang Y, Vavvas D et al. Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. Oncotarget. 2017;8(20):32794-32806. https://doi.org/10.18632/oncotarget.15825
Ying, Ying ; Ueta, Takashi ; Jiang, Shanshan ; Lin, Hui ; Wang, Yuanyuan ; Vavvas, Demetrios ; Wen, Rong ; Chen, Ye Guang ; Luo, Zhijun. / Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. In: Oncotarget. 2017 ; Vol. 8, No. 20. pp. 32794-32806.
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