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Antagomir-mediated silencing of endothelial cell specific microRNA-126 impairs ischemia-induced angiogenesis

Author: Solingen, C. van · Seghers, L. · Bijkerk, R. · Duijs, J.M.G.J. · Roeten, M.K. · Oeveren van - Rietdijk, A.M. · Baelde, H.J. · Monge, M. · Vos, J.B. · Boer, H.C. de · Quax, P.H.A. · Rabelink, T.J. · Zonneveld, A.J. van
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Journal of Cellular and Molecular Medicine, 8 A, 13, 1577-1585
Identifier: 241974
doi: doi:10.1111/j.1582-4934.2008.00613.x
Keywords: Biomedical Research · Angiogenesis · Endothelial function · Ischemia · MicroRNA · Vascular biology

Abstract

MicroRNAs are negative regulators of gene expression that play a key role in cell-type specific differentiation and modulation of cell function and have been proposed to be involved in neovascularization. Previously, using an extensive cloning and sequencing approach, we identified miR-126 to be specifically and highly expressed in human endothelial cells (EC). Here, we demonstrate EC-specific expression of miR-126 in capillaries and the larger vessels in vivo. We therefore explored the potential role of miR-126 in arteriogenesis and angiogenesis. Using miR-reporter constructs, we show that miR-126 is functionally active in EC in vitro and that it could be specifically repressed using antagomirs specifically targeting miR-126. To study the consequences of miR-126 silencing on vascular regeneration, mice were injected with a single dose of antagomir-126 or a control 'scramblemir' and exposed to ischemia of the left hindlimb by ligation of the femoral artery. Although miR-126 was effectively silenced in mice treated with a single, high dose (HD) of antagomir-126, laser Doppler perfusion imaging did not show effects on blood flow recovery. In contrast, quantification of the capillary density in the gastrocnemius muscle revealed that mice treated with a HD of antagomir-126 had a markedly reduced angiogenic response. Aortic explant cultures of the mice confirmed the role of miR-126 in angiogenesis. Our data demonstrate a facilitary function for miR-126 in ischemia-induced angiogenesis and show the efficacy and specificity of antagomir-induced silencing of EC-specific microRNAs in vivo. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.