Toxic damage increases angiogenesis and metastasis in fibrotic livers via PECAM-1

Biomed Res Int. 2014;2014:712893. doi: 10.1155/2014/712893. Epub 2014 Mar 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Ethanol / toxicity*
  • Fibrosis
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunohistochemistry
  • Liver / pathology*
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Metastasis
  • Neovascularization, Pathologic*
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Ethanol