Published Online
on June 1, 2004

A more recent version of this article appeared on June 15, 2004

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Submitted on July 22, 2003
Revised on March 9, 2004
Accepted on March 9, 2004

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal-Regulated Kinase Activation

Plinio Cirillo MD, PhD, Gaetano Calì PhD, Paolo Golino MD, PhD^*, Paolo Calabrò MD, Lavinia Forte MD, Salvatore De Rosa MD, Mario Pacileo MD, Massimo Ragni MD, PhD, Francesco Scopacasa MD, Lucio Nitsch MD, and Massimo Chiariello MD

From the Division of Cardiology (P. Cirillo, P. Calabrò, S.D., M.P., M.R., M.C.), Department of Biology and Cellular and Molecular Pathology "L. Califano" (L.N.), and Department of Biochemistry and Biotechnology (F.S.), University of Naples "Federico II"; Division of Cardiology, Second University of Naples (P.G., L.F.); and IEOS "G. Salvatore"-National Council of Research (G.C.), Naples, Italy.

^* To whom correspondence should be addressed. E-mail: paolo.golino{at}unina2.it.

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.

Methods and 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.

Key words: coagulants • signal transduction • cell division

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