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-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.

Propofol attenuated TNF-α-modulated occludin expression by inhibiting Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway in hCMEC/D3 cells

“…It has been reported that VEGF could activate ERK pathway via the activation of VEGF receptor-2(VEGFR-2) [20]. As shown in Fig.…”

Propofol attenuated the effect of TNF-α on occludin expression by inhibiting HIF-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells

“…It has been reported that VEGF could activate ERK pathway via activation of VEGF receptor-2(VEGFR-2) [ 19]. As shown in Fig.…”

Regenerative Potential of Carbon Monoxide in Adult Neural Circuits of the Central Nervous System

“…PI3K-Akt activation can induce endothelial cell survival and angiogenesis, as well as NSC survival and neurogenesis [114][115][116]. Akt phosphorylation by PI3Ks influences important diverse downstream signals, including endothelial NOS (eNOS), mTOR, glycogen synthase kinase-3β (GSK3β) and other signaling molecules [114,117] (Figure 2). In the CNS, genetic activation of the PI3K-Akt-mTOR pathway, through deficiencies in upstream negative regulators (i.e., phosphatase, PTEN, hamartin (tuberous sclerosis complex 1 (TSC1)) and tuberin (TSC2)), increases the axon regeneration capacity [118,119].…”