VASCULAR BIOLOGY Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells

MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression on the posttranscriptional level. The miR-17-92 cluster (encoding miR-17, -18a, -19a/b, -20a, and miR-92a) is highly expressed in tumor cells and is upregulated by ischemia. Whereas miR-92a was recently identified as negative regulator of angiogenesis, the specific functions of the other members of the cluster are less clear. Here we demonstrate that overexpression of miR-17, -18a, -19a, and -20a significantly inhibited 3-dimensional spheroid sprouting in vitro, whereas inhibition of miR-17, -18a, and -20a augmented endothelialcell sprout formation. Inhibition of miR-17 andmiR-20a invivousingantagomirssignificantly increased the number of perfused vessels in Matrigel plugs, whereas antagomirs that specifically target miR-18a and miR-19a were less effective. However, systemic inhibition of miR-17/20 did not affect tumor angiogenesis. Further mechanistic studies showed that miR-17/20 targets several proangiogenic genes. Specifically, Janus kinase 1 was shown to be a direct target of miR-17. In summary, we show that miR17/20 exhibit a cell-intrinsic antiangiogenic activity in endothelial cells. Inhibition of miR17/20 specifically augmented neovascularization of Matrigel plugs but did not affect tumor angiogenesis indicating a contextdependent regulation of angiogenesis by miR-17/20 in vivo. (Blood. 2010;115(23): 4944-4950)