Thrombomodulin overexpression to limit neointima formation

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

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

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 0.767±0.06%, whereas viral controls reached 0.77±0.08%; in contrast, Adv/RSV-THM reduced UM 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.

Original languageEnglish (US)
Pages (from-to)332-337
Number of pages6
JournalCirculation
Volume102
Issue number3
DOIs
StatePublished - Jul 18 2000
Externally publishedYes

Keywords

  • Extracellular matrix
  • Gene therapy
  • Inflammation
  • Thrombosis
  • Viruses

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Waugh, J. M., Li-Hawkins, J., Yuksel, E., Kuo, M. D., Cifra, P. N., Hilfiker, P. R., Geske, R., Chawla, M., Thomas, J., Shenaq, S. M., Dake, M. D., & Woo, S. L. C. (2000). Thrombomodulin overexpression to limit neointima formation. Circulation, 102(3), 332-337. https://doi.org/10.1161/01.CIR.102.3.332