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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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-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.

Original languageEnglish
Pages (from-to)474-483
Number of pages10
JournalBiomolecules and Therapeutics
Volume27
Issue number5
DOIs
Publication statusPublished - 2019 Sep

Fingerprint

Vascular Endothelial Growth Factor Receptor-2
Choroidal Neovascularization
Vascular Endothelial Growth Factor A
Permeability
Vascular Endothelial Growth Factor Receptor
Endothelial cells
Capillary Permeability
Endothelial Cells
Blood Vessels
Claudin-5
Pathologic Neovascularization
Catenins
Phosphorylation
Nitric Oxide Synthase Type III
Therapeutic Uses
Endothelium
Actins
Lasers
Chemical activation
arginyl-leucyl-tyrosyl-glutamic acid

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Park, Wonjin ; Baek, Yi Yong ; Kim, Joohwan ; Jo, Dong Hyun ; Choi, Seunghwan ; Kim, Jin Hyoung ; Kim, Taesam ; Kim, Suji ; Park, Minsik ; Kim, Ji Yoon ; Won, Moo Ho ; Ha, Kwon Soo ; Kim, Jeong Hun ; Kwon, Young Guen ; Kim, Young Myeong. / Arg-leu-tyr-glu suppresses retinal endothelial permeability and choroidal neovascularization by inhibiting the VEGF receptor 2 signaling pathway. In: Biomolecules and Therapeutics. 2019 ; Vol. 27, No. 5. pp. 474-483.
@article{ec59491c51434e3bad4012debbf578bc,
title = "Arg-leu-tyr-glu suppresses retinal endothelial permeability and choroidal neovascularization by inhibiting the VEGF receptor 2 signaling pathway",
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-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.",
author = "Wonjin Park and Baek, {Yi Yong} and Joohwan Kim and Jo, {Dong Hyun} and Seunghwan Choi and Kim, {Jin Hyoung} and Taesam Kim and Suji Kim and Minsik Park and Kim, {Ji Yoon} and Won, {Moo Ho} and Ha, {Kwon Soo} and Kim, {Jeong Hun} and Kwon, {Young Guen} and Kim, {Young Myeong}",
year = "2019",
month = "9",
doi = "10.4062/biomolther.2019.041",
language = "English",
volume = "27",
pages = "474--483",
journal = "Biomolecules and Therapeutics",
issn = "1976-9148",
publisher = "Korean Society of Applied Pharmacology",
number = "5",

}

Park, W, Baek, YY, Kim, J, Jo, DH, Choi, S, Kim, JH, Kim, T, Kim, S, Park, M, Kim, JY, Won, MH, Ha, KS, Kim, JH, Kwon, YG & Kim, YM 2019, 'Arg-leu-tyr-glu suppresses retinal endothelial permeability and choroidal neovascularization by inhibiting the VEGF receptor 2 signaling pathway', Biomolecules and Therapeutics, vol. 27, no. 5, pp. 474-483. https://doi.org/10.4062/biomolther.2019.041

Arg-leu-tyr-glu suppresses retinal endothelial permeability and choroidal neovascularization by inhibiting the VEGF receptor 2 signaling pathway. / Park, Wonjin; Baek, Yi Yong; Kim, Joohwan; Jo, Dong Hyun; Choi, Seunghwan; Kim, Jin Hyoung; Kim, Taesam; Kim, Suji; Park, Minsik; Kim, Ji Yoon; Won, Moo Ho; Ha, Kwon Soo; Kim, Jeong Hun; Kwon, Young Guen; Kim, Young Myeong.

In: Biomolecules and Therapeutics, Vol. 27, No. 5, 09.2019, p. 474-483.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Arg-leu-tyr-glu suppresses retinal endothelial permeability and choroidal neovascularization by inhibiting the VEGF receptor 2 signaling pathway

AU - Park, Wonjin

AU - Baek, Yi Yong

AU - Kim, Joohwan

AU - Jo, Dong Hyun

AU - Choi, Seunghwan

AU - Kim, Jin Hyoung

AU - Kim, Taesam

AU - Kim, Suji

AU - Park, Minsik

AU - Kim, Ji Yoon

AU - Won, Moo Ho

AU - Ha, Kwon Soo

AU - Kim, Jeong Hun

AU - Kwon, Young Guen

AU - Kim, Young Myeong

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85068845436&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068845436&partnerID=8YFLogxK

U2 - 10.4062/biomolther.2019.041

DO - 10.4062/biomolther.2019.041

M3 - Article

AN - SCOPUS:85068845436

VL - 27

SP - 474

EP - 483

JO - Biomolecules and Therapeutics

JF - Biomolecules and Therapeutics

SN - 1976-9148

IS - 5

ER -