Signal transducer and activator of transcription 1 activation in endothelial cells is a negative regulator of angiogenesis.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Traci E
TE
Battle
Rebecca A
RA
Lynch
David A
DA
Frank
D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma; D040301:Vascular Endothelial Growth Factor Receptor-2