Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form-a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. Thus, an adenoviral construct expressing thrombomodulin was created and functionally characterized in vitro and in vivo. The impact of local overexprcssion of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi (p<0.01 vs viral and nonviral controls); overall mean cross sectional percent thrombus was 4.70+/ -1.07 for thrombomodulin treatments, while nonviral controls were 71.62+/ -5.70 and viral controls were 89.1 +/-3.43. No significant alterations in degree of overall inflammation or intima to media ratio were observed in the thrombomodulin group relative to controls. This construct thus offers a viable technique for promoting a locally thromboresistant small caliber artery, without the inflammatory damage that has limited many other adenoviral applications.
|State||Published - 20 Mar 1998|