Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway
Wonjin Park1, Yi-Yong Baek1, Joohwan Kim1, Dong Hyun Jo2, Seunghwan Choi1, Jin Hyoung Kim2, Taesam Kim1, Suji Kim1, Minsik Park1, Ji Yoon Kim3, Moo-Ho Won4, Kwon-Soo Ha1, Jeong Hun Kim2, Young-Guen Kwon5 and Young-Myeong Kim1,*
1Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 24341,
2Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080,
3Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul 04763,
4Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 24341,
5Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
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Received: March 7, 2019; Revised: April 2, 2019; Accepted: April 4, 2019; Published online: May 2, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGFA-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, β-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.
Keywords: VEGF, VEGFR2, Choroidal neovascularization, Macular degeneration, Vascular leakage, Permeability

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