Endothelial to mesenchymal transition (EndoMT) has been proposed to be involved in the loss of microvascular
capillaries in the pathophysiology of fibrosis and organ failure. In EndoMT, endothelial cells (EC) undergo a mesenchymal
transition associated with the loss of cell-cell contacts and the acquisition of a synthetic, contractile phenotype.
Here, we sought to identify microRNAs (miRNAs) that could play a central role in regulating EndoMT. In a TGF-β dependent
in vitro model for EndoMT, we identified miRNAs that were differentially expressed in normoxic and hypoxic
conditions. These studies identified miR-155 to be significantly upregulated in EndoMT, an effect that was enhanced under
hypoxia, which further augments EndoMT. Silencing of miR-155 directly increased RhoA expression and activity in
endothelial cells and affected phosphorylation of downstream LIMK. In contrast, overexpression of miR-155 counteracted
RhoA function. Using a selective Rho kinase inhibitor, we could partly suppress EndoMT, strengthening the notion that
RhoA plays a central role in EndoMT. Forced overexpression of miR-155 completely suppressed EndoMT, as evidenced
by the maintenance of EC characteristics and blocking the acquisition of a mesenchymal phenotype, as compared to control
cells. Our data demonstrate that miRNA-155 functions as a negative regulator of RhoA signaling in TGF-β-induced
endothelial to mesenchymal transition.
Keywords: microRNA, microRNA-155, EndoMT, antagomiR, RhoA, TGFβ, hypoxia, phosphorylation, mesenchymal, cytoskeleton.
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