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Monique David-Dufilho, Olivier Schussler, Marie-Gabrielle Pernollet, Annie Brunet, Elisabeth Millanvoye-Van Brussel, Kim Hahn Le Quan Sang, Francine Rendu
Therapeutic immunoglobulin reduces Ca2+ mobilization and von Willebrand factor secretion, and increases nitric oxide release in human endothelial cells
Intravenous -immunoglobulin (IVIg) is commonly used in the treatment of autoimmune and inflammatory vascular disorders to prevent thrombotic complications. The mechanism of action of IVIg is, however, not yet elucidated. In view of this, we investigated the ability of IVIg to modulate i) Ca2+ signals of fura-2 loaded endothelial cells, and ii) the associated release of nitric oxide (NO) and von Willebrand factor (vWf). NO was measured either indirectly by radioimmunoassay of cGMP in unstimulated cells or directly by electrochemistry at the surface of stimulated endothelial cells from human umbilical cord veins (HUVEC). Short-term treatment of unstimulated HUVEC with intact IVIg decreased the basal cytosolic Ca2+ concentration by 20% while it activated the NO/cGMP synthesis. Following IVIg treatment of HUVEC, the Ca2+ liberation from internal stores and the vWf secretion induced by ATP, thrombin or histamine were significantly reduced by 38 and 60 %, respectively. The effects on Ca2+ signals were observed with intact IVIg as well as with the F(ab')2 or the Fc fragments indicating that both portions are involved in the mechanism of action. The IVIg treatment of HUVECs had no effect on the NO release induced by thrombin or histamine. By contrast, the IVIg treatment increased the ATP-activated NO release by amplifying the Ser1177-eNOS phosphorylation. The IVIg also activated the NO-dependent cGMP release in resting and collagen-stimulated platelets. Since NO is a potent inhibitor of platelet activation and vWF is a platelet adhesion cofactor, the beneficial effects of therapeutic IVIg may lie in the inhibition of platelet adhesion to damaged endothelium.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 90, 12/2003
Pages: 1046 - 1053