Abstract
BackgroundMicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated.Methodology/Principal FindingsWe first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization.Conclusions/SignificanceOur results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB.
Highlights
Over the past few decades, microRNAs have emerged as a prominent class of gene regulators. miRNAs are endogenous small single-strand non-coding RNAs of about 22 nucleotides [1]
Together with a protein complex known as RNAinduced silencing complex (RISC), miRNA functions as a guide molecule in post-transcriptional gene silencing by partially complementing to the 39 untranslated region (UTR) of target mRNA
In order to determine a potential role for miR-21 in angiogenesis, we analyzed the impact of growth factor treatment on miR-21 expression in human umbilical vein endothelial cells (HUVECs). miR-21 abundance was first analyzed in HUVECs cultured in endothelial basal medium lacking growth factors and serum or in basal medium supplemented with serum and a cocktail of angiogenic factors
Summary
Over the past few decades, microRNAs (miRNAs) have emerged as a prominent class of gene regulators. miRNAs are endogenous small single-strand non-coding RNAs of about 22 nucleotides [1]. Over the past few decades, microRNAs (miRNAs) have emerged as a prominent class of gene regulators. MiRNAs are endogenous small single-strand non-coding RNAs of about 22 nucleotides [1]. Together with a protein complex known as RNAinduced silencing complex (RISC), miRNA functions as a guide molecule in post-transcriptional gene silencing by partially complementing to the 39 untranslated region (UTR) of target mRNA. Each miRNA can regulate up to hundreds of targets and miRNAs are predicted to regulate a third of protein coding genes [3]. By regulating numerous mRNAs, miRNAs play a key role in a wide range of physiological and pathological processes [4,5]. MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated
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