title: Toxic damage increases angiogenesis and metastasis in fibrotic livers via PECAM-1.
abstract: Excessive ethanol consumption is one of the main causes of liver fibrosis. However, direct effects of ethanol exposure on endothelial cells and their contribution to fibrogenesis and metastasis were not investigated. Therefore we analysed whether ethanol directly affects endothelial cells and if this plays a role during fibrogenesis and metastasis in the liver. Murine and human endothelial cells were exposed to ethanol for up to 72 hours. In vitro, effects on VEGF, HIF-1alpha, PECAM-1, and endothelial cell functions were analysed. In vivo, effects of continuous liver damage on blood vessel formation and metastasis were analysed by PECAM-1 immunohistochemistry. Ethanol increased HIF-1alpha and VEGF levels in murine and human endothelial cells. This resulted in enhanced intracellular signal transduction, and PECAM-1 expression as well as tube formation and wound healing. In vivo, toxic liver damage increased angiogenesis during fibrogenesis. Metastasis was also enhanced in fibrotic livers and located to PECAM-1 positive blood vessels compared to nonfibrotic mice. In conclusion, ethanol had strong effects on endothelial cells, which--at least in part--led to a profibrotic and prometastatic environment mediated by PECAM-1. Blockade of increased PECAM-1 expression could be a promising tool to inhibit fibrogenesis and metastasis in the liver.
authors.affiliation: Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Raskopf
authors.affiliation: Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Gonzalez Carmona
authors.affiliation: Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany.
authors.forename: Christina Jay
authors.initials: CJ
authors.lastname: Van Cayzeele
authors.affiliation: Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Strassburg
authors.affiliation: Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.affiliation: Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany ; Krankenhaus Marienwörth, Mühlenstraße 39, 55543 Bad Kreuznach, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity*; D005355:Fibrosis; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000431:Ethanol
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