IONIZING IRRADIATION INCREASES TRANSCRIPTION OF THE VON-WILLEBRAND-FACTOR GENE IN ENDOTHELIAL-CELLS

Ionizing irradiation damage to the vasculature results in an increase in procoagulant activity of endothelial cells, including elevated von Willebrand factor (vWf) secretion. We investigated the mechanism of ir radiation induction of vWf release and demonstrated that vWf mRNA leve ls were increased when either human or bovine endothelial cells were e xposed to 20 Gy irradiation. This response to irradiation was independ ent of de novo protein synthesis, but required new transcription. Nucl ear run-on experiments indicated that increased vWf transcriptional ac tivity was partly responsible for the higher levels of the mRNA accumu lation. Transfection analyses with plasmids in which a human growth ho rmone structural gene was under the control of the endothelial-cell-sp ecific vWf promoter demonstrated that irradiation increased promoter a ctivity. Deletion analyses demonstrated that sequences necessary for i rradiation induction of the promoter activity were located within the 112-bp sequences (-90 to +22) that constitute the non-endothelial-cell -specific core promoter region of the vWf gene. Results of gel mobilit y assays and deletion analyses demonstrated that a site in the vWf pro moter other than the putative NF-kB binding site is involved in the me chanism of irradiation induction of the vWf. (C) 1996 by The American Society of Hematology.