Tissue factor binding of activated factor VII triggers smooth muscle cell proliferation via extracellular signal-regulated kinase activation.
BACKGROUND
Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation.


RESULTS
Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3H]thymidine incorporation and direct cell counting, whereas no response was observed with active site-inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1.


CONCLUSIONS
These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis.
Cirillo
Plinio
P
Division of Cardiology, University of Naples Federico II, Italy.
Calì
Gaetano
G
Golino
Paolo
P
Calabrò
Paolo
P
Forte
Lavinia
L
De Rosa
Salvatore
S
Pacileo
Mario
M
Ragni
Massimo
M
Scopacasa
Francesco
F
Nitsch
Lucio
L
Chiariello
Massimo
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology; D001161:Arteriosclerosis / Q000378:metabolism; D001665:Binding Sites; D001777:Blood Coagulation; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015942:Factor VIIa / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013925:Thromboplastin / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D011993:Recombinant Fusion Proteins; C113580:U 0126; D013925:Thromboplastin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015942:Factor VIIa