REACTIVE OXYGEN INTERMEDIATES INDUCE REGULATED SECRETION OF VON-WILLEBRAND-FACTOR FROM CULTURED HUMAN VASCULAR ENDOTHELIAL-CELLS

Exocytosis from Weibel-Palade bodies, the secretory granules of vascul ar endothelial cells, causes the rapid release of von Willebrand facto r (VWF), an adhesive glycoprotein involved in primary hemostasis, and cell surface expression of P-selectin, a membrane protein involved in neutrophil binding. Thus, exocytosis may represent a link between hemo stasis and inflammation. We investigated the effect of reactive oxygen intermediates (ROIs) on VWF secretion. Incubation of cultured endothe lial cells with xanthine oxidase (XO), which generates superoxide anio ns (O-2(-)), induces a potent, rapid secretory response. However, vWF release was not observed in response to H2O2. Extracellular, subendoth elial vWF deposits typically seen after exocytosis from Weibel-Palade bodies were observed after exposure to XO, XO caused a rapid, sustaine d increase in intracellular free calcium concentration ([Ca2+](i)). vW F secretion was markedly inhibited by BAPTA-AM, a cell-permeant calciu m chelator, Removal of extracellular calcium did not inhibit vWF relea se, although the sustained phase of the [Ca2+](i) increase was suppres sed, These results suggest that XO-induced vWF release is mediated by the initial increase in [Ca2+](i) which is caused by calcium mobilizat ion from intracellular stores rather than by calcium influx, Exocytosi s from Weibel-Palade bodies may contribute to the pathogenic effect of ROIs in atherosclerosis and inflammation. (C) 1995 by The American So ciety of Hematology.