Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1

Vascular endothelial cell growth factor (VEGF) is a major regulator of angi ogenesis. We report here that treatment of endothelial cells with VEGF lead s to upregulation of tissue factor mRNA and protein expression on the cell surface. Reporter gene studies show that transcriptional activation of the tissue factor gene by VEGF is mediated by a GC-rich promoter element contai ning overlapping binding sites for Spl and EGR-1. As shown by immunofluores cence and electrophoretic mobility shift assays, upon VEGF treatment EGR-1 rapidly accumulates in the nucleus and binds to its respective recognition site in the tissue factor promoter. Spl occupies this element in unstimulat ed cells and seems to be partially displaced by increasing amounts of EGR-1 . Transfection of endothelial cells with an EGR-1 expression plasmid mimics the upregulation of tissue factor transcription observed after VEGF treatm ent. In contrast, NF kappa B, the major transcription factor involved in ti ssue factor upregulation by inflammatory stimuli, is not activated by VEGF. These data show that VEGF induces a response in endothelial cells largely distinct from inflammatory stimuli, and suggest that EGR-1 is a major media tor of the activation of the tissue factor and possibly other VEGF-responsi ve genes. (C) 1999 by The American Society of Hematology.