1.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
Biomolecules & Therapeutics 2019;27(5):474-483
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.
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