Tissue factor is not involved in the mitogenic activity of factor VIIa

The present study was undertaken to evaluate in vitro the importance of tis sue factor in the mitogenic effect of factor VIIa for embryonic fibroblasts . For that purpose, embryonic fibroblasts were isolated from either wild-ty pe or transgenic mice showing a single inactivation of the tissue factor ge ne or expressing a truncated form (lacking the cytosolic domain) of this pr otein. Factor Wa stimulated in a dose-dependent manner the growth of the 3 types of fibroblasts, thus showing that TF is not involved in the mitogenic activity of factor VIIa. The mitogenic activity of factor Wa disappeared i n serum immunopurified in factor X and was almost totally inhibited by DX90 65, a selective factor Xa inhibitor, showing that this effect of factor Wa occurred via factor Xa generated during the incubation period. Hirudin did not show any significant effect on factor VIIa-induced fibroblast prolifera tion, thus showing that the effect observed for factor VIIa was selectively mediated by factor Xa and was not due to thrombin formation. Our results t herefore represent the first evidence for the possible importance of factor Xa in the mitogenic effect of factor VIIa and show the negligible role of tissue factor in this process. (C) 2001 Academic Press.