Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease

Abstract

Abstract Placental growth factor (Pl GF ) is a member of the vascular endothelial growth factor ( VEGF ) family and is involved in pathological angiogenesis associated with chronic liver diseases. However, the precise mechanisms underlying Pl GF signalling contributing to liver fibrosis and angiogenesis remain largely unexplored. This study aimed to assess the effect of reducing Pl GF expression using small interfering RNA (si RNA ) on experimental liver fibrosis and angiogenesis, and to elucidate the underlying molecular mechanisms. Fibrosis was induced in mice by carbon tetrachloride ( CC l 4 ) for 8 weeks, and mice were treated with Pl GF si RNA or non‐targeting control si RNA starting two weeks after initiating CC l 4 injections. The results showed that Pl GF was highly expressed in cirrhotic human and mice livers; which mainly distributed in activated hepatic stellate cells ( HSC s). Pl GF silencing robustly reduced liver inflammation, fibrosis, intrahepatic macrophage recruitment, and inhibited the activation of HSC s in vivo . Moreover, Pl GF si RNA ‐treated fibrotic mice showed diminished hepatic microvessel density and angiogenic factors, such as hypoxia‐inducible factor‐1α ( HIF ‐1α), VEGF and VEGF receptor‐1. Moreover, down‐regulation of Pl GF with si RNA in HSC s inhibited the activation and proliferation of HSC s. Mechanistically, overexpression of Pl GF in activated HSC s was induced by hypoxia dependent on HIF ‐1α, and Pl GF induces HSC activation and proliferation via activation the phosphatidylinositol 3‐kinase ( PI 3K)/Akt signalling pathways. These findings indicate that Pl GF plays an important role in liver fibrosis‐associated angiogenesis and that blockage of Pl GF could be an effective strategy for chronic liver disease.