Tissue factor is not involved in the mitogenic activity of factor VIIa.
The present study was undertaken to evaluate in vitro the importance of tissue factor in the mitogenic effect of factor VIIa for embryonic fibroblasts. For that purpose, embryonic fibroblasts were isolated from either wild-type or transgenic mice showing a single inactivation of the tissue factor gene or expressing a truncated form (lacking the cytosolic domain) of this protein. Factor VIIa 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 VIIa disappeared in serum immunopurified in factor X and was almost totally inhibited by DX9065, a selective factor Xa inhibitor, showing that this effect of factor VIIa occurred via factor Xa generated during the incubation period. Hirudin did not show any significant effect on factor VIIa-induced fibroblast proliferation, thus showing that the effect observed for factor VIIa was selectively mediated by factor Xa and was not due to thrombin formation. Our results therefore 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.
Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo Recherche, Toulouse, France. jean-marc.herbert@sanofi-synthelabo.com
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JM
Herbert
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de Prost
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Ollivier
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Melis
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Carmeliet
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015942:Factor VIIa / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006629:Hirudins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000502:physiology*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D006629:Hirudins; D009281:Naphthalenes; D011422:Propionates; D013925:Thromboplastin; D015942:Factor VIIa