Oleanolic Acids Inhibit Vascular Endothelial Growth Factor Receptor 2 Signaling in Endothelial Cells: Implication for Anti-Angiogenic Therapy
Da-Hye Lee1,2, Jungsul Lee3,4, Jongwook Jeon5, Kyung-Jin Kim1, Jang-Hyuk Yun1, Han-Seok Jeong1,2, Eun Hui Lee6, Young Jun Koh7,*, and Chung-Hyun Cho1,2,*
1Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Korea, 2Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea, 3Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea, 4Cellex Life Science Inc., Daejeon 34051, Korea, 5The Korean Research Institute of Science, Technology and Civilization, Chonbuk National University, Jeonju 54896, Korea, 6Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea, 7Department of Pathology, College of Korean Medicine, Dongguk University, Goyang 10326, Korea
*Correspondence: iamhyun@snu.ac.kr (CHC); youngjun.koh@dongguk.edu (YJK)
Received May 14, 2018; Revised June 14, 2018; Accepted June 20, 2018.; Published online July 24, 2018.
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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


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31 July 2018 Volume 41,
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