Liver fibrosis is a common feature of liver dysfunction during chronic liver diseases and is frequently associated with angiogenesis, a dynamic process that forms new blood vessels from preexisting vasculature. MicroRNAs (miRNAs), which act as posttranscriptional regulators of gene expression, have been shown to regulate liver fibrosis; however, how miRNAs regulate angiogenesis and its mechanism in fibrosis are not well understood. We aimed to elucidate the role and mechanism of miR-30c in attenuating liver fibrosis. Using miRNA profiling of fibrotic murine livers, we identified differentially regulated miRNAs and discovered that miR-30c is aberrantly expressed and targets endothelial delta-like ligand 4 (DLL4) in either carbon tetrachloride-treated or bile duct ligated fibrotic mice, as well as in patients with liver fibrosis. Using CCK-8, wound healing and Matrigel tube formation assays, we found that miR-30c inhibited liver sinusoidal endothelial cell (LSEC) proliferation, migration, and angiogenesis capacity by targeting DLL4 in vitro. Importantly, nanoparticle-based delivery of miR-30c to LSECs inhibited the DLL4/Notch pathway and angiogenesis, thereby ameliorating liver fibrosis in vivo. Collectively, our findings demonstrate a protective role of miR-30c in liver fibrosis by regulating DLL4/Notch signaling and angiogenesis. Thus, miR-30c may serve as a potential treatment for chronic liver diseases.
Keywords: delta-like ligand 4; liver fibrosis; liver sinusoidal endothelial cell; miR-30c.
© 2021 Federation of American Societies for Experimental Biology.