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Oleanolic Acids Inhibit Vascular Endothelial Growth Factor Receptor 2 Signaling in Endothelial Cells: Implication for Anti-Angiogenic Therapy

  • Lee, Da-Hye (Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University) ;
  • Lee, Jungsul (Department of Bio and Brain Engineering, KAIST) ;
  • Jeon, Jongwook (The Korean Research Institute of Science, Technology and Civilization, Chonbuk National University) ;
  • Kim, Kyung-Jin (Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University) ;
  • Yun, Jang-Hyuk (Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University) ;
  • Jeong, Han-Seok (Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University) ;
  • Lee, Eun Hui (Department of Physiology, College of Medicine, The Catholic University of Korea) ;
  • Koh, Young Jun (Department of Pathology, College of Korean Medicine, Dongguk University) ;
  • Cho, Chung-Hyun (Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University)
  • Received : 2018.05.14
  • Accepted : 2018.06.20
  • Published : 2018.08.31

Abstract

Angiogenesis must be precisely controlled because uncontrolled angiogenesis is involved in aggravation of disease symptoms. Vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) signaling is a key pathway leading to angiogenic responses in vascular endothelial cells (ECs). Therefore, targeting VEGF/VEGFR-2 signaling may be effective at modulating angiogenesis to alleviate various disease symptoms. Oleanolic acid was verified as a VEGFR-2 binding chemical from anticancer herbs with similar binding affinity as a reference drug in the Protein Data Bank (PDB) entry 3CJG of model A coordination. Oleanolic acid effectively inhibited VEGF-induced VEGFR-2 activation and angiogenesis in HUVECs without cytotoxicity. We also verified that oleanolic acid inhibits in vivo angiogenesis during the development and the course of the retinopathy of prematurity (ROP) model in the mouse retina. Taken together, our results suggest a potential therapeutic benefit of oleanolic acid for inhibiting angiogenesis in proangiogenic diseases, including retinopathy.

Keywords

angiogenesis;endothelial cells;oleanolic acid;retinopathy of prematurity;VEGFR-2

Acknowledgement

Supported by : National Research Foundation of Korea, SNUH

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