Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway
10.4062/biomolther.2019.041
- Author:
Wonjin PARK
1
;
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
Author Information
1. Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea. ymkim@kangwon.ac.kr
- Publication Type:Original Article
- Keywords:
VEGF;
VEGFR2;
Choroidal neovascularization;
Macular degeneration;
Vascular leakage;
Permeability
- MeSH:
Actins;
Animals;
Capillary Permeability;
Choroid;
Choroidal Neovascularization;
Claudin-5;
Endothelial Cells;
Endothelium;
Humans;
Macular Degeneration;
Mice;
Nitric Oxide Synthase Type III;
Permeability;
Phosphorylation;
Receptors, Vascular Endothelial Growth Factor;
Retinaldehyde;
Vascular Endothelial Growth Factor A
- From:Biomolecules & Therapeutics
2019;27(5):474-483
- CountryRepublic of Korea
- Language:English
-
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, 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.
