Arg-leu-tyr-glu suppresses retinal endothelial permeability and choroidal neovascularization by inhibiting the VEGF receptor 2 signaling pathway

Wonjin Park, Yi Yong Baek, Joohwan Kim, Dong Hyun Jo, Seunghwan Choi, Jin Hyoung Kim, Taesam Kim, Suji Kim, Minsik Park, Ji Yoon Kim, Moo Ho Won, Kwon Soo Ha, Jeong Hun Kim, Young Guen Kwon, Young Myeong Kim

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6 Citations (Scopus)


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-Ainduced 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.

Original languageEnglish
Pages (from-to)474-483
Number of pages10
JournalBiomolecules and Therapeutics
Issue number5
Publication statusPublished - 2019 Sep

Bibliographical note

Funding Information:
This study has been worked with the support of a research grant of Kangwon National University in 2019. This work was also supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) (2017R1A2B3004565, 2017R1A2B3004565, and 2015M3A9E6028949).

Publisher Copyright:
© 2019 The Korean Society of Applied Pharmacology.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery


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