Human plasminogen-derived N-acetyl-Arg-Leu-Tyr-Glu antagonizes VEGFR-2 to prevent blood-retinal barrier breakdown in diabetic mice

https://doi.org/10.1016/j.biopha.2020.111110Get rights and content
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Highlights

  • Novel tetrapeptide Ac-RLYE antagonizes VEGFR-2-mediated signaling.

  • Ac-RLYE prevents VEGF-A-induced endothelial NO production and barrier disruption.

  • It protects the vascular integrity and prevents leakage in diabetic mice retinas.

  • This peptide can be used as a VEGFR-2 antagonist for the treatment of PDR.

Abstract

Targeting the vascular endothelial growth factor (VEGF)/its receptor-2 (VEGFR-2) system has become a mainstay of treatment for many human diseases, including retinal diseases. We examined the therapeutic effect of recently developed N-acetylated Arg-Leu-Tyr-Glu (Ac-RLYE), a human plasminogen kringle-5 domain-derived VEGFR-2 antagonists, on the pathogenesis of diabetic retinopathy. Ac-RLYE inhibited VEGF-A-mediated VEGFR-2 activation and endothelial nitric oxide synthase (eNOS)-derived NO production in the retinas of diabetic mice. In addition, Ac-RLYE prevented the disruption of adherens and tight junctions and vascular leakage by inhibiting S-nitrosylation of β-catenin and tyrosine nitration of p190RhoGAP in the retinal vasculature of diabetic mice. Peptide treatment preserved the pericyte coverage of retinal capillaries by upregulating angiopoietin-2. These results suggest that Ac-RLYE potentially prevents blood-retinal barrier breakdown and vascular leakage by antagonizing VEGFR-2; Ac-RLYE can be used as a potential therapeutic drug for the treatment of diabetic retinopathy.

Abbreviations

VEGF-A
vascular endothelial growth factor-A
VEGFR-1
vascular endothelial growth factor receptor-1
VEGFR-2
vascular endothelial growth factor receptor-2
Ac-RLYE
N-acetyl-Arg-Leu-Tyr-Glu
Ang1
angiopoietin-1
Ang2
angiopoietin-2
eNOS
endothelial nitric oxide synthase
NO
nitric oxide
DR
diabetic retinopathy
NPDR
non-proliferative diabetic retinopathy
PDR
proliferative diabetic retinopathy
BRB
blood-retinal barrier
EC
endothelial cell
AJ
adherens junction
TJ
tight junction
L-NIO
N5-(1-iminoethyl)-1-ornithine dihydrochloride
VE-cadherin
vascular endothelial cadherin
ZO-1
zonula occluden 1
HRMEC
human retinal microvascular endothelial cell
FBS
foetal bovine serum
STZ
streptozotocin
HFD
high-fat diet
PFA
paraformaldehyde
DAPI
4’6-diamidino-2-phenylindole
NG2
neuron-glial antigen 2

Keywords

VEGFR-2 antagonist
Vascular leakage
Blood-retinal barrier
Diabetic retinopathy

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