MicroRNA-18a improves human cerebral arteriovenous malformation endothelial cell function.
Stroke
; 45(1): 293-7, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-24203843
ABSTRACT
BACKGROUND AND PURPOSE:
Cerebral arteriovenous malformation (AVM) is a vascular disease that disrupts normal blood flow and leads to serious neurological impairment or death. Aberrant functions of AVM-derived brain endothelial cells (AVM-BECs) are a disease hallmark. Our aim was to use microRNA-18a (miR-18a) as a therapeutic agent to improve AVM-BEC function.METHODS:
Human AVM-BECs were tested for growth factor production and proliferation under different shear flow conditions and evaluated for tubule formation. Thrombospondin-1, inhibitor of DNA-binding protein 1, and vascular endothelial growth factor (VEGF) isotype mRNA levels were quantified by quantitative real-time polymerase chain reaction. Thrombospondin-1, VEGF-A, and VEGF-D protein expression was measured using enzyme-linked immunosorbent assay. Proliferation and tubule formation were evaluated using bromodeoxyuridine incorporation and growth factor-reduced Matrigel assays, respectively.RESULTS:
miR-18a increased thrombospondin-1 production but decreased inhibitor of DNA-binding protein 1, a transcriptional repressor of thrombospondin-1. miR-18a reduced VEGF-A and VEGF-D levels, both overexpressed in untreated AVM-BECs. This is the first study reporting VEGF-D overexpression in AVM. These effects were most prominent under arterial shear flow conditions. miR-18a also reduced AVM-BEC proliferation, improved tubule formation, and was effectively internalized by AVM-BECs in the absence of extraneous transfection reagents.CONCLUSIONS:
We report VEGF-D overexpression in AVM and the capacity of miR-18a to induce AVM-BECs to function more normally. This highlights the clinical potential of microRNA as a treatment for AVM and other vascular diseases.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Malformações Vasculares do Sistema Nervoso Central
/
MicroRNAs
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Células Endoteliais
Limite:
Humans
Idioma:
En
Revista:
Stroke
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Canadá