{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:46:54Z","timestamp":1790282814587,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,1,31]],"date-time":"2017-01-31T00:00:00Z","timestamp":1485820800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:sec><jats:title>BACKGROUND AND PURPOSE<\/jats:title><jats:p>Hepatic stellate cells (HSCs) are liver\u2010specific pericytes regulating angiogenesis during liver fibrosis. We aimed to elucidate the mechanisms by which hedgehog signalling regulated HSC angiogenic properties and to validate the therapeutic implications.<\/jats:p><\/jats:sec><jats:sec><jats:title>EXPERIMENTAL APPROACH<\/jats:title><jats:p>Rats and mice were treated with carbon tetrachloride for <jats:italic>in vivo<\/jats:italic> evaluation of hepatic angiogenesis and fibrotic injury. Diversified molecular approaches including real\u2010time PCR, Western blot, luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay and co\u2010immunoprecipitation were used to investigate the underlying mechanisms <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>KEY RESULTS<\/jats:title><jats:p>Angiogenesis was concomitant with up\u2010regulation of Smoothened (SMO) and hypoxia inducible factor\u20101\u03b1 (HIF\u20101\u03b1) in rat fibrotic liver. The SMO inhibitor cyclopamine and Gli1 inhibitor GANT\u201058 reduced expression of VEGF and angiopoietin 1 in HSCs and suppressed HSC tubulogenesis capacity. HIF\u20101\u03b1 inhibitor PX\u2010478 suppressed HSC angiogenic behaviour, and inhibition of hedgehog decreased HIF\u20101\u03b1 expression. Furthermore, heat shock protein 90 (HSP90) was characterized as a direct target gene of canonical hedgehog signalling in HSCs. HSP90 inhibitor 17\u2010AAG reduced HSP90 binding to HIF\u20101\u03b1, down\u2010regulated HIF\u20101\u03b1 protein abundance and decreased HIF\u20101\u03b1 binding to DNA. 17\u2010AAG also abolished 1\u2010stearoyl\u20102\u2010arachidonoyl\u2010sn\u2010glycerol (SAG) (a SMO agonist)\u2010enhanced HSC angiogenic properties. Finally, the natural compound ligustrazine was found to inhibit canonical hedgehog signalling leading to suppressed angiogenic properties of HSCs <jats:italic>in vitro<\/jats:italic> and ameliorated liver fibrosis and sinusoidal angiogenesis in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION AND IMPLICATIONS<\/jats:title><jats:p>We have provided evidence that the canonical hedgehog pathway controlled HSC\u2010mediated liver angiogenesis. Selective inhibition of HSC hedgehog signalling could be a promising therapeutic approach for hepatic fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13701","type":"journal-article","created":{"date-parts":[[2017,1,4]],"date-time":"2017-01-04T07:16:39Z","timestamp":1483514199000},"page":"409-423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Canonical hedgehog signalling regulates hepatic stellate cell\u2010mediated angiogenesis in liver fibrosis"],"prefix":"10.1111","volume":"174","author":[{"given":"Feng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine Nanjing 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