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We previously demonstrated that hedgehog signaling promoted proliferation and inhibited apoptosis in hepatic stellate cells. This study was aimed to evaluate the effect of tetramethylpyrazine (TMP) on hedgehog signaling and to further examine the molecular mechanisms of TMP\u2010induced antiangiogenesic effects in liver fibrosis. We found that TMP ameliorated the expression of proangiogenic markers vascular endothelial growth factor A (VEGF\u2010A), vascular endothelial growth factor receptor 2 (VEGF\u2010R2), platelet\u2010derived growth factor BB (PDGF\u2010BB), platelet\u2010derived growth factor\u2010\u03b2 receptor (PDGF\u2010\u03b2R) and hypoxia inducible factor 1\u03b1 (HIF\u20101\u03b1), concomitant with reduced abundance of endothelial markers platelet endothelial cell adhesion molecule\u20101 (PECAM\u20101\/CD31), CD34 and von willebrand factor <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Interestingly, TMP attenuated the abundance of sonic hedgehog, smoothened (Smo) and glioblastoma but increased the expression of hedgehog\u2010interacting protein in liver sinusoidal endothelial cells, which was underlying mechanism for the antiangiogenesic activity of TMP. Downregulation of Smo activity, using selective Smo inhibitor cyclopamine, lead to a synergistic effect with TMP, whereas Smo overexpression plasmid impaired the induction of antiangiogenesic effects of TMP. Overall, these results provide novel implications to reveal the molecular mechanism of TMP\u2010inhibited liver sinusoidal angiogenesis, by which points to the possibility of using TMP\u2010based antiangiogenic drugs for the treatment of liver fibrosis. \u00a9 2017 IUBMB Life, 69(2):115\u2013127, 2017<\/jats:p>","DOI":"10.1002\/iub.1598","type":"journal-article","created":{"date-parts":[[2017,1,23]],"date-time":"2017-01-23T11:26:58Z","timestamp":1485170818000},"page":"115-127","source":"Crossref","is-referenced-by-count":44,"title":["Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis"],"prefix":"10.1002","volume":"69","author":[{"given":"Shifeng","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zili","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangjuan","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine Saint Louis University St Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy Nanjing University of Chinese Medicine Nanjing People's Republic of China"},{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese Medicine Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,1,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.04.018"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.03.039"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27296"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1089\/jmf.2015.0104"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep11734"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2013.03.004"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/8617062"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.12537"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1348"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12818"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2015.10.002"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2015.2"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-015-9488-z"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00306"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-306294"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.025"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2575"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8342"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27635"},{"key":"e_1_2_7_21_1","first-page":"1599","article-title":"Pharmacokinetics studies on tetramethylpyrazine by intravenous administration in rats","volume":"33","author":"Chen H. 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