Back to Search Start Over

In vitro and in vivo inhibition of proangiogenic retinal phenotype by an antisense oligonucleotide downregulating uPAR expression.

Authors :
Lulli M
Cammalleri M
Granucci I
Witort E
Bono S
Di Gesualdo F
Lupia A
Loffredo R
Casini G
Dal Monte M
Capaccioli S
Source :
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2017 Aug 26; Vol. 490 (3), pp. 977-983. Date of Electronic Publication: 2017 Jun 27.
Publication Year :
2017

Abstract

Neoangiogenesis is the main pathogenic event involved in a variety of retinal diseases. It has been recently demonstrated that inhibiting the urokinase-type plasminogen activator receptor (uPAR) results in reduced angiogenesis in a mouse model of oxygen-induced retinopathy (OIR), establishing uPAR as a therapeutic target in proliferative retinopathies. Here, we evaluated in cultured human retinal endothelial cells (HRECs) and in OIR mice the potential of a specific antisense oligodeoxyribonucleotide (ASO) in blocking the synthesis of uPAR and in providing antiangiogenic effects. uPAR expression in HRECs was inhibited by lipofection with the phosphorotioated 5'-CGGCGGGTGACCCATGTG-3' ASO-uPAR, complementary to the initial translation site of uPAR mRNA. Inhibition of uPAR expression via ASO-uPAR was evaluated in HRECs by analyzing VEGF-induced tube formation and migration. In addition, the well-established and reproducible murine OIR model was used to induce retinal neovascularization in vivo. OIR mice were injected intraperitoneally with ASO-uPAR and retinopathy was evaluated considering the extent of the avascular area in the central retina and neovascular tuft formation. The ASO-uPAR specifically decreased uPAR mRNA and protein levels in HRECs and mitigated VEGF-induced tube formation and cell migration. Noteworthy, in OIR mice ASO-uPAR administration reduced both the avascular area and the formation of neovascular tufts. In conclusion, although the extrapolation of these experimental findings to the clinic is not straightforward, ASO-uPAR may be considered a potential therapeutic tool for treatment of proliferative retinal diseases.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1090-2104
Volume :
490
Issue :
3
Database :
MEDLINE
Journal :
Biochemical and biophysical research communications
Publication Type :
Academic Journal
Accession number :
28666875
Full Text :
https://doi.org/10.1016/j.bbrc.2017.06.150