title: 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: 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 CCl4injections. 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.
authors.affiliation: Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University and Shanghai Institute of Liver Diseases, Shanghai, China.
authors.forename: Qun-Yan
authors.initials: QY
authors.lastname: Yao
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University and Shanghai Institute of Liver Diseases, Shanghai, China.
authors.forename: Hong-Chun
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University and Shanghai Institute of Liver Diseases, Shanghai, China.
authors.forename: Qian-Wen
authors.initials: QW
authors.lastname: Jin
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University and Shanghai Institute of Liver Diseases, Shanghai, China.
authors.forename: Bei-Li
authors.initials: BL
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University and Shanghai Institute of Liver Diseases, Shanghai, China.
authors.forename: Shun-Cai
authors.initials: SC
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University and Shanghai Institute of Liver Diseases, Shanghai, China.
authors.forename: Chuan-Tao
authors.identifier: 0000-0002-9106-9868
authors.initials: CT
authors.lastname: Tu
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D000072483:Placenta Growth Factor / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000072483:Placenta Growth Factor; D002251:Carbon Tetrachloride
keywords: angiogenesis; cirrhosis; hepatic fibrosis; hepatic stellate cells; placental growth factor; small interfering RNA