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(Circulation Research. 2005;97:293.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Vascular Remodeling in Mice Lacking the Cytoplasmic Domain of Tissue Factor

Ilka Ott, Cornelia Michaelis, Maren Schuermann, Birgit Steppich, Isabell Seitz, Mieke Dewerchin, Dietlind Zohlnhofer, Rainer Wessely, Martina Rudelius, Albert Schömig, Peter Carmeliet

From the Deutsches Herzzentrum und 1. Medizinische Klinik der Technischen Universität München (I.O., C.M., M.S., B.S., I.S., D.Z., R.W., A.S.), Germany; Zentrum für präklinische Forschung, Klinikum rechts der Isar der Technischen Universität München (C.M., M.S.), Germany; Center for Transgene Technology and Gene Therapy (M.D., P.C.), Leuven, Belgium; Institut für Pathologie (M.R.), Klinikum rechts der Isar der Technischen Universität München, Germany

Correspondence to I. Ott, Deutsches Herzzentrum, Lazarettstr. 36, 80636 München, Germany. E-mail ott{at}dhm.mhn.de

Tissue factor (TF), the cell surface receptor for the serine protease FVIIa supports cell migration by interaction with the cytoskeleton. Intracellular signaling pathways dependent on the cytoplasmic domain of TF modify cell migration and may alter vascular remodeling. Vascular remodeling was analyzed in a femoral artery injury and a blood flow cessation model in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids of TF (TF^ct/ct) and compared with TF wild-type mice (TF^wt/wt). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TF^ct/ct compared with TF^wt/wt mice (femoral artery injury: 2.4±0.3 TF^wt/wt versus 0.6±0.3 TF^ct/ct, n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TF^wt/wt versus 0.22+0.03 TF^ct/ct, n=12 to 14, P=0.09). This was caused by an increase in the media by 54% (P=0.04) in the femoral artery model and by 32% (P=0.03) after carotis ligation and was associated with an increased number of proliferating cells. Isolated aortic smooth muscle cells (SMCs) of TF^wt/wt mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TF^ct/ct SMC. In contrast, the unstimulated proliferation rate was increased in TF^ct/ct SMC compared with TF^wt/wt SMCs. Thus, retention of SMCs attributable to a migratory defect and increased proliferation results in thickening of the media and in decrease in neointima formation after arterial injury. TF cytoplasmic domain signaling alters vascular remodeling and, thereby, may play a role in the development of restenosis, atherosclerotic disease, and neovascularization.

Key Words: arterial injury • tissue factor • smooth muscle cells • restenosis

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