ABSTRACT FINAL ID: 1698
TITLE: PlGF silencing ameliorates hepatic angiogenesis in mice with liver fibrosis induced by carbon tetrachloride
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This work was supported by the National Natural Science Foundation of China, grant number 81170398.
Background & aims: Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. The present study was aimed to assess the role of PlGF in liver fibrosis-associated angiogenesis and analyzed the effect of reducing the expression of PlGF by means of RNA silencing (siRNA) on hepatic angiogenesis in mice with liver fibrosis. Methods: Mice were induced liver fibrosis by carbon tetrachloride (CCl4) for eight weeks together with PlGF-siRNA or with nontargeting control siRNA. Liver fibrosis was determined by quantitation of Sirius red staining, histological fibrotic scoring, hepatic hydroxyproline content, and collagen type III expression. The activation of HSC was investigated by analysis of α-smooth muscle actin (α-SMA) expression in vivo and in vitro. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, F4/80, and hypoxia-inducible factor-1α immunostaining or western blot respectively. Furthermore, the mRNA and proteins levels of proangiogenic and inflammatory cytokines factors, including vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), NRP-1, intercellular adhesion molecule-1 (ICAM-1), the interferon-inducible chemokine CXCL10, and CCL2 were analyzed by quantitative RT-PCR, Western blot, or immunohistochemistry. Results: We found that PlGF silencing significantly reduced hepatic inflammation, hepatic fibrosis, and inhibition the activation HSC. Moreover, mice with fibrosis treated with the PlGF silencing showed diminished hepatic microvessel density. In addition, PlGF silencing suppressed expression of CXCL10, MCP-1, ICAM-1, VEGF, VEGFR2, and NRP-1. Conclusion: Our findings indicate that PlGF exerts strong fibrogenic and angiogenic effects in a model of experimental liver fibrosis. The amelioration of fibrosis-associated angiogenesis liver by PlGF knockdown suggest that targeting PlGF has therapeutic potential for chronic liver diseases associated with increased neoangiogenesis.