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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1653-1661.
Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-04-1148.


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GENE THERAPY

Inhibition of restenosis by tissue factor pathway inhibitor: in vivo and in vitro evidence for suppressed monocyte chemoattraction and reduced gelatinolytic activity

Christoph W. Kopp, Thomas Hölzenbein, Sabine Steiner, Rodrig Marculescu, Helga Bergmeister, Daniela Seidinger, Isabella Mosberger, Christoph Kaun, Manfred Cejna, Reinhard Horvat, Johann Wojta, Gerald Maurer, Bernd R. Binder, Johannes M. Breuss, Rupert C. Ecker, Rainer de Martin, and Erich Minar

From the 2nd Department of Medicine, Division of Angiology and Cardiology, the Departments of Vascular Surgery, Laboratory Medicine, Biomedical Research, Angiography and Interventional Radiology, Pathology, and Vascular Biology and Thrombosis Research, University of Vienna Medical School, Vienna, Austria; and the Competence Center Bio Molecular Therapeutics, Vienna, Austria.

Activation of inflammatory and procoagulant mechanisms is thought to contribute significantly to the initiation of restenosis, a common complication after balloon angioplasty of obstructed arteries. During this process, expression of tissue factor (TF) represents one of the major physiologic triggers of coagulation that results in thrombus formation and the generation of additional signals leading to vascular smooth muscle cell (VSMC) proliferation and migration. In this study, we have investigated the mechanisms by which inhibition of coagulation at an early stage through overexpression of tissue factor pathway inhibitor (TFPI), an endogenous inhibitor of TF, might reduce restenosis. In a rabbit femoral artery model, percutaneous delivery of TFPI using a recombinant adenoviral vector resulted in a significant reduction of the intimamedia ratio 21 days after injury. Investigating several markers of inflammation and coagulation, we found reduced neointimal expression of monocyte chemoattractant protein-1 (MCP-1), lesional monocyte infiltration, and expression of vascular TF, matrix metalloproteinase-2 (MMP-2), and MMP-9. Moreover, overexpression of TFPI suppressed the autocrine release of platelet-derived growth factor BB (PDGF-BB), MCP-1, and MMP-2 in response to factors VIIa and Xa from VSMCs in vitro and inhibited monocyte TF activity. These results suggest that TFPI exerts its action in vivo through not only thrombotic, but also nonthrombotic mechanisms.


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