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Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway
Biomolecules & Therapeutics ; : 474-483, 2019.
Article in English | WPRIM | ID: wpr-763034
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.
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Full text: Available Index: WPRIM (Western Pacific) Main subject: Permeability / Phosphorylation / Retinaldehyde / Capillary Permeability / Choroid / Actins / Choroidal Neovascularization / Receptors, Vascular Endothelial Growth Factor / Endothelial Cells / Vascular Endothelial Growth Factor A Limits: Animals / Humans Language: English Journal: Biomolecules & Therapeutics Year: 2019 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Permeability / Phosphorylation / Retinaldehyde / Capillary Permeability / Choroid / Actins / Choroidal Neovascularization / Receptors, Vascular Endothelial Growth Factor / Endothelial Cells / Vascular Endothelial Growth Factor A Limits: Animals / Humans Language: English Journal: Biomolecules & Therapeutics Year: 2019 Type: Article