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KMID : 0606920190270050474
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Biomolecules & Therapeutics
2019 Volume.27 No. 5 p.474 ~ p.483
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Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway
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Park Won-Jin
Baek Yi-Yong
Kim Joo-Hwan
Jo Dong-Hyun
Choi Seung-Hwan
Kim Jin-Hyoung
Kim Tae-Sam
Kim Su-Ji
Park Min-Sik
Kim Ji-Yoon
Won Moo-Ho
Ha Kwon-Soo
Kim Jeong-Hun
Kwon Young-Guen
Kim Young-Myeong
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Abstract
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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.
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KEYWORD
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VEGF, VEGFR2, Choroidal neovascularization, Macular degeneration, Vascular leakage, Permeability
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