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(Circulation Research. 2001;89:71.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Role for Tissue Factor Pathway in Murine Model of Vascular Remodeling

Ripudamanjit Singh, Shuchong Pan, Cheryl S. Mueske, Tyra Witt, Laurel S. Kleppe, Timothy E. Peterson, Adriana Slobodova, Jen-Yea Chang, Noel M. Caplice, Robert D. Simari

From the Department of Internal Medicine and Cardiovascular Disease, Department of Biochemistry and Molecular Biology, Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, Minn, and the Center for Thrombosis and Hemostasis (J.-Y.C.), University of North Carolina, Chapel Hill, NC.

Correspondence to Robert D. Simari, MD, Mayo Clinic and Foundation, GU 1801, 200 First St SW, Rochester, MN 55905. E-mail simari.robert{at}mayo.edu

Abstract

Abstract—Tissue factor (TF) is a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade and is considered a major regulator of arterial thrombogenicity. TF pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. The aim of this study was to define the complex interplay between TF and TFPI and the regulation of vascular thrombogenicity in a model of vascular remodeling. To determine the levels and pattern of vascular expression of TF and TFPI associated with vascular remodeling, a murine model of flow cessation was studied. TF activity of the arteries increased after ligation (P<0.05). Quantitative analysis of homogenates of remodeled carotid arteries revealed increased TF expression but unchanged TFPI expression compared with normal carotid arteries, resulting in enhanced TF activity. To determine the potential therapeutic role of TFPI in this thrombogenic state, mice were treated with intravascular adenoviral delivery of either murine TFPI (Ad-mTFPImyc) or a control adenovirus (Ad-E1). Overexpression of TFPI decreased vascular TF activity compared with viral control (P<0.01). Overexpression of TFPI inhibited neointimal formation (P=0.038), resulting in enhanced luminal area (P=0.001) 4 weeks after flow cessation. In this murine model of vascular remodeling, an imbalance between TF and TFPI expression is generated, resulting in increased TF activity. Overexpression of TFPI in this model inhibits vascular TF activity and results in attenuation of vascular remodeling associated with flow interruption.

Key Words: thrombosis • arteriosclerosis • gene therapy

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