Thrombomodulin overexpression to limit neointima formation

Background-These studies were initiated to confirm that high-level thrombom odulin overexpression is sufficient to limit neointima formation after mech anical overdilation injury. Methods and Results-An adenoviral construct expressing thrombomodulin (AdV/ RSV-THM) was created and functionally characterized in vitro and in vivo. T he impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand Whi te 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 t o determine intima-to-media (I/M) ratios, Additional experiments were perfo rmed to determine early (7-day) changes in extracellular elastin and collag en content; local macrophage, T-cell, and neutrophil infiltration; and loca l thrombus formation as potential contributors to the observed impact on 28 -day neointima formation. The construct significantly decreased neointima f ormation after mechanical dilation injury in this model. By histological an alysis, buffer controls exhibited mean UM ratios of 0.76 +/- 0.06%, whereas viral controls reached 0.77 +/- 0.08%; in contrast, Adv/RSV-THM reduced VM ratios to 0.47 +/- 0.06%. Local inflammatory infiltrate decreased in the A dv/RSV-THM group relative to controls, whereas matrix remained relatively p reserved. Rates of early thrombus formation also decreased in AdV/RSV-THM a nimals. Conclusions-This construct thus offers a viable technique for promoting a l ocally 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.