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(Circulation. 2004;109:2911-2916.)
© 2004 American Heart Association, Inc.

Basic Science Reports

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; 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.

Correspondence to Paolo Golino, MD, PhD, Division of Cardiology, Second University of Naples, c/o Ospedale Monaldi, Via Leonardo Bianchi, 80131 Naples, Italy. E-mail paolo.golino{at}unina2.it

Received July 22, 2003; de novo received December 5, 2003; revision received March 9, 2004; accepted March 9, 2004.

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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