Signal transducer and activator of transcription 1 activation in endothelial cells is a negative regulator of angiogenesis

Cancer Res. 2006 Apr 1;66(7):3649-57. doi: 10.1158/0008-5472.CAN-05-3612.

Abstract

To determine the role of the transcription factor signal transducer and activator of transcription (STAT) 1 on endothelial cell function, human umbilical vein endothelial cells (HUVEC) were treated with IFN-gamma, a potent activator of STAT1. IFN-gamma inhibited cell growth and tube formation of HUVECs. Although the potent proangiogenic protein vascular endothelial growth factor (VEGF) stimulated cell growth and tube formation, IFN-gamma could suppress these effects of VEGF. Transfection of HUVECs with short interfering RNA targeting STAT1 abrogated IFN-gamma-induced inhibition of HUVEC growth and tube formation, and suppressed the inhibition of VEGF-induced tube formation by IFN-gamma, indicating that STAT1 is critical for this process. IFN-gamma blocks the biological activity of VEGF through inhibition of genes necessary for the VEGF response, including angiopoietin-2, urokinase plasminogen activator, tissue inhibitor of matrix metalloproteinase-1, cyclooxygenase-2, and VEGF receptor 2. To extend these findings in vivo, the role of STAT1 in angiogenesis was examined in STAT1-deficient mice using the Matrigel in vivo angiogenesis assay. Substantial cellular infiltration and formation of vascular structures occurred in STAT1-/- mice compared with wild-type controls. These data indicate that STAT1 plays a key role in the inhibition of angiogenesis through its action within endothelial cells, and exploiting this process may be useful in treating cancers and vascular tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Growth Processes / drug effects
  • Cell Growth Processes / physiology
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Humans
  • Interferon-gamma / pharmacology
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Phosphorylation / drug effects
  • RNA, Small Interfering / genetics
  • Recombinant Proteins
  • STAT1 Transcription Factor / antagonists & inhibitors
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Transfection
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • RNA, Small Interfering
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Vascular Endothelial Growth Factor A
  • Interferon-gamma
  • Vascular Endothelial Growth Factor Receptor-2