© 2000 American Heart Association, Inc.
Thrombosis |
Vascular Endothelial Growth Factor Production by Fibroblasts in Response to Factor VIIa Binding to Tissue Factor Involves Thrombin and Factor Xa
From INSERM U479 (V.O., J.H., D.d.P.), Faculté Xavier Bichat, Paris; LFB Recherche et Développement (J.C.), Les Ulis; Haemobiology Research Department (J.M.H.), Sanofi Recherche, Toulouse; and Service d’Hématologie et d’Immunologie Biologiques (D.d.P.), Hôpital Louis Mourier, AP-HP, Colombes, France.
Correspondence to Dr D. de Prost, Hôpital Louis Mourier, Service d’Hématologie et d’Immunologie Biologiques, 178, rue des Renouillers, 92700 Colombes, France. E-mail dominique.de-prost{at}lmr.ap-hop-paris.fr
Abstract—Tissue factor (TF) assembled with activated factor VII (FVIIa) initiates the coagulation cascade. We recently showed that TF was essential for FVIIa-induced vascular endothelial growth factor (VEGF) production by human fibroblasts. We investigated whether this production resulted from TF activation by its binding to FVIIa or from the production of clotting factors activated downstream. Incubation of fibroblasts with a plasma-derived FVIIa concentrate induced the generation of activated factor X (FXa) and thrombin and the secretion of VEGF, which was inhibited by hirudin and FXa inhibitors. By contrast, the addition of recombinant FVIIa to fibroblasts did not induce VEGF secretion unless factor X was present. Moreover, thrombin and FXa induced VEGF secretion and VEGF mRNA accumulation, which were blocked by hirudin and FXa inhibitors, respectively. The effect of thrombin was mediated by its specific receptor, protease-activated receptor-1; in contrast, the effect of FXa did not appear to involve effector cell protease receptor-1, because it was not affected by an anti–effector cell protease receptor-1 antibody. An increase in intracellular calcium with the calcium ionophore A23187 or intracellular calcium chelation by BAPTA-AM had no effect on either basal or FXa-induced VEGF secretion, suggesting that the calcium signaling pathway was not sufficient to induce VEGF secretion. Finally, FVIIa, by itself, had no effect on mitogen-activated protein (MAP) kinase activation, contrary to thrombin and FXa, which activate the p44/p42 MAP kinase pathway, as shown by the blocking effect of PD 98059 and by Western blotting of activated MAP kinases. These findings indicate that FVIIa protease induction of VEGF expression is mediated by thrombin and FXa generated in response to FVIIa binding to TF-expressing fibroblasts; they also exclude a direct signaling involving MAP kinase activation via the intracellular domain of TF when expressed by these cells.
Key Words: vascular endothelial growth factor • tissue factor • activated factor VII • fibroblasts • proteases
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