Biomol Ther.
2019 Sep;27(5):474-483. 10.4062/biomolther.2019.041.
Arg-Leu-Tyr-Glu Suppresses Retinal Endothelial Permeability and Choroidal Neovascularization by Inhibiting the VEGF Receptor 2 Signaling Pathway
- Affiliations
-
- 1Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea. ymkim@kangwon.ac.kr
- 2Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.
- 3Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul 04763, Republic of Korea.
- 4Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea.
- 5Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
- KMID: 2456222
- DOI: http://doi.org/10.4062/biomolther.2019.041
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.
Keyword
MeSH Terms
-
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*
Actins
Claudin-5
Nitric Oxide Synthase Type III
Receptors, Vascular Endothelial Growth Factor
Retinaldehyde
Vascular Endothelial Growth Factor A
- Full Text Links
-
- Actions
-
Cited
- CITED
-
- Close
- Share
-
- Similar articles
-
- The Role of VEGF and Bruch's Membrane in the Development Choroidal Neovascularization
- Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis
- Vitreous Vascular Endothelial Growth Factor Concentration In Various Vitreoretinal Disorders
- Anti-Vascular Endothelial Growth Factor Therapy for Choroidal Neovascularization Secondary to Optic Nerve Head Drusen
- Delay of Spontaneous Neutrophil Apoptosis by Vascular Endothelial Growth Factor
