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(Circulation. 2000;102:332.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Thrombomodulin Overexpression to Limit Neointima Formation

J. M. Waugh, MD; J. Li-Hawkins, PhD; E. Yuksel, MD; M. D. Kuo, MD; P. N. Cifra, BA; P. R. Hilfiker, MD; R. Geske, BS; M. Chawla, MD; J. Thomas, MD; S. M. Shenaq, MD; M. D. Dake, MD; S. L. C. Woo, PhD

From the Department of Cell Biology (J.M.W., J.L.-H., S.L.C.W.), Division of Plastic Surgery (E.Y., P.N.C., S.M.S.), and Department of Comparative Medicine (R.G.), Baylor College of Medicine, Houston, Tex; Stanford Institute of Bioengineering and Molecular Medicine and Department of Radiology, Stanford University School of Medicine, Stanford, Calif (J.M.W., M.D.K., P.R.H., M.D.D.); Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas (J.L.-H.); and Department of Radiology, MD Anderson Cancer Center, Houston, Tex (M.C., J.T.).

Correspondence to Savio L.C. Woo, PhD, Institute for Gene Therapy and Molecular Medicine, Mt Sinai School of Medicine, Box 1496, One Gustave L. Levy Place, New York, NY 10029. E-mail swoo{at}smtplink.mssm.edu

Background—These studies were initiated to confirm that high-level thrombomodulin overexpression is sufficient to limit neointima formation after mechanical overdilation injury.

Methods and Results—An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand White rabbit common femoral arteries were treated with buffer, viral control, or Adv/RSV-THM and subjected to mechanical overdilation injury. The treated vessels (n=4 per treatment) were harvested after 28 days and evaluated to determine intima-to-media (I/M) ratios. Additional experiments were performed to determine early (7-day) changes in extracellular elastin and collagen content; local macrophage, T-cell, and neutrophil infiltration; and local thrombus formation as potential contributors to the observed impact on 28-day neointima formation. The construct significantly decreased neointima formation after mechanical dilation injury in this model. By histological analysis, buffer controls exhibited mean I/M ratios of 0.76±0.06%, whereas viral controls reached 0.77±0.08%; in contrast, Adv/RSV-THM reduced I/M ratios to 0.47±0.06%. Local inflammatory infiltrate decreased in the Adv/RSV-THM group relative to controls, whereas matrix remained relatively preserved. Rates of early thrombus formation also decreased in Adv/RSV-THM animals.

Conclusions—This construct thus offers a viable technique for promoting a locally neointima-resistant small-caliber artery via decreased thrombus bulk, normal matrix preservation, and decreased local inflammation without the inflammatory damage that has limited many other adenoviral applications.

Key Words: gene therapy • extracellular matrix • viruses • inflammation • thrombosis

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