Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway

  • Park, Wonjin (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Baek, Yi-Yong (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Joohwan (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Jo, Dong Hyun (Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital) ;
  • Choi, Seunghwan (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Jin Hyoung (Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital) ;
  • Kim, Taesam (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Suji (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Park, Minsik (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Ji Yoon (Department of Anesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Won, Moo-Ho (Department of Neurobiology, School of Medicine, Kangwon National University) ;
  • Ha, Kwon-Soo (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Kim, Jeong Hun (Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital) ;
  • Kwon, Young-Guen (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Kim, Young-Myeong (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University)
  • Received : 2019.03.07
  • Accepted : 2019.04.04
  • Published : 2019.09.01
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Abstract

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 VEGF-A-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, ${\beta}$-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

References

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