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

• Published in: Journal of cellular and molecular medicine Vol. 21; no. 10; pp. 2370 - 2385
• Main Authors: Li, Xi, Yao, Qun‐Yan, Liu, Hong‐Chun, Jin, Qian‐Wen, Xu, Bei‐Li, Zhang, Shun‐Cai, Tu, Chuan‐Tao
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2017; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Animal models; Animals; Carbon Tetrachloride; CCL4 protein; Cell activation; Cell Proliferation - genetics; Cells, Cultured; Chronic Disease; cirrhosis; Disease Models, Animal; Down-regulation; Fibrosis; hepatic fibrosis; hepatic stellate cells; Hepatic Stellate Cells - metabolism; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Liver Cirrhosis - chemically induced; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver diseases; Liver Diseases - genetics; Liver Diseases - metabolism; Macrophages; Male; Mice, Inbred BALB C; Molecular modelling; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Original; Placenta; Placenta Growth Factor - genetics; Placenta Growth Factor - metabolism; placental growth factor; Rats, Sprague-Dawley; RNA Interference; Rodents; Signal transduction; Signal Transduction - genetics; siRNA; small interfering RNA; Stellate cells; Vascular endothelial growth factor; placental growth factor; hepatic stellate cells; small interfering RNA; hepatic fibrosis; angiogenesis; cirrhosis
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.13158

Placental growth factor (PlGF) 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 PlGF signalling contributing to liver fibrosis and angiogenesis remain largely unexplored. This study aimed to assess the effect of reducing PlGF expression using small interfering RNA (siRNA) on experimental liver fibrosis and angiogenesis, and to elucidate the underlying molecular mechanisms. Fibrosis was induced in mice by carbon tetrachloride (CCl4) for 8 weeks, and mice were treated with PlGF siRNA or non‐targeting control siRNA starting two weeks after initiating CCl4 injections. The results showed that PlGF was highly expressed in cirrhotic human and mice livers; which mainly distributed in activated hepatic stellate cells (HSCs). PlGF silencing robustly reduced liver inflammation, fibrosis, intrahepatic macrophage recruitment, and inhibited the activation of HSCs in vivo. Moreover, PlGF siRNA‐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 PlGF with siRNA in HSCs inhibited the activation and proliferation of HSCs. Mechanistically, overexpression of PlGF in activated HSCs was induced by hypoxia dependent on HIF‐1α, and PlGF induces HSC activation and proliferation via activation the phosphatidylinositol 3‐kinase (PI3K)/Akt signalling pathways. These findings indicate that PlGF plays an important role in liver fibrosis‐associated angiogenesis and that blockage of PlGF could be an effective strategy for chronic liver disease.