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

拮抗剂 血管生成 小RNA 基因沉默 动脉发生 新生血管 细胞生物学 生物 Wnt信号通路 癌症研究 体内 信号转导 基因 遗传学
作者
Coen van Solingen,Leonard Seghers,Roel Bijkerk,Jacques M.G.J. Duijs,Marko K. Roeten,Annemarie M. van Oeveren-Rietdijk,Hans J. Baelde,Matthieu Monge,Joost B. Vos,Hetty C. de Boer,Paul H.A. Quax,Ton J. Rabelink,Anton Jan van Zonneveld
出处
期刊:Journal of Cellular and Molecular Medicine [Wiley]
卷期号:13 (8a): 1577-1585 被引量:233
标识
DOI:10.1111/j.1582-4934.2008.00613.x
摘要

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.
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