Early-response gene signalling is induced by angiogenic oligosaccharides of hyaluronan in endothelial cells. Inhibition by non-angiogenic, high-molecular-weight hyaluronan

Int J Cancer. 1997 Apr 10;71(2):251-6. doi: 10.1002/(sici)1097-0215(19970410)71:2<251::aid-ijc21>3.0.co;2-j.


The degradation products of hyaluronan are known to stimulate endothelial-cell proliferation and to promote neovascularization associated with angiogenesis, whilst native high-molecular-weight hyaluronan is inhibitory to these processes. To investigate the cellular signalling pathways coupled to hyaluronan-induced responses in angiogenesis, we have analyzed early-response gene expression in vitro, in cultured bovine aortic endothelial cells. Angiogenic oligosaccharides of hyaluronan induced rapid transient up-regulation of the immediate early genes c-fos, c-jun, jun-B, Krox-20 and Krox-24. In contrast, native hyaluronan when used alone failed to elicit a significant change in expression of any of the genes tested, and when used in combination with angiogenic oligosaccharides of hyaluronan, gave a dose-dependent inhibition of induced gene expression. However, prior addition of angiogenic hyaluronan, as little as one minute before addition of high-molecular-weight hyaluronan, abrogated this inhibition, suggesting that positive or negative responses associated with hyaluronan signalling are integrated at a very early stage following receptor binding. Conversely, prior addition of high-molecular-weight hyaluronan led to an irreversible block in gene expression and proliferative response. These data are consistent with native hyaluronan antagonizing the angiogenic response in part by blocking a signalling cascade at or immediately following ligand-receptor interaction. Finally, we demonstrated that chronic exposure to oligosaccharides of hyaluronan is essential for cell proliferation, indicating that short-term immediate early-gene signalling is insufficient to elicit the proliferation of endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cell Division / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Early Growth Response Protein 2
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Gene Expression Regulation*
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / pharmacology*
  • Immediate-Early Proteins / metabolism*
  • Immunohistochemistry
  • Neovascularization, Physiologic / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Transcription Factors / metabolism
  • Up-Regulation


  • DNA-Binding Proteins
  • Early Growth Response Protein 2
  • Hyaluronan Receptors
  • Immediate-Early Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Transcription Factors
  • Hyaluronic Acid