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In vitro and in vivo inhibition of proangiogenic retinal phenotype by an antisense oligonucleotide downregulating uPAR expression.
- 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.)
- Subjects :
- Angiogenesis Inhibitors genetics
Animals
Cell Line
Cell Movement drug effects
Disease Models, Animal
Genetic Therapy
Humans
Mice
Oligodeoxyribonucleotides, Antisense genetics
RNA, Messenger genetics
Receptors, Urokinase Plasminogen Activator analysis
Receptors, Urokinase Plasminogen Activator metabolism
Retina cytology
Retina metabolism
Retinal Neovascularization metabolism
Retinal Neovascularization pathology
Vascular Endothelial Growth Factor A metabolism
Angiogenesis Inhibitors therapeutic use
Oligodeoxyribonucleotides, Antisense therapeutic use
Receptors, Urokinase Plasminogen Activator genetics
Retina pathology
Retinal Neovascularization genetics
Retinal Neovascularization therapy
Subjects
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