Enhanced expression of tissue factor activity in the atherosclerotic aortas of cholesterol-fed rabbits

Tissue factor (TF) is an initiation cofactor of the extrinsic pathway of coagulation. Although the overexpression of TF antigen and mRNA have been previously demonstrated in atherosclerotic lesions using both immunohistochemical and in situ hybridization techniques, it still remains unclear as to whether TF activity is overexpressed in atherosclerotic plaque in vivo. In thoracic aortas obtained from cholesterol-fed rabbits for 10-20 weeks, the TF-mediated activation of factor X was quantitatively assessed on the intimal surface of the aortas ex vivo using a chromogenic substrate S-2222 and the findings were then compared with the immunohistochemical distribution of TF antigen. Non-atherosclerotic intimas showed only a weak amount of TF activity, while the adventitia contained a significantly high amount of activity. In the atherosclerotic intimas where TF antigen was overexpressed by foamy and non-foamy macrophages and smooth muscle cells but not by endothelial cells, TF activity was apparently enhanced to a level similar to that in the adventitia. Scanning electron microscopy revealed a perturbation of the intimal surface of the atherosclerotic aorta. These findings suggest that TF activity is apparently enhanced in subendothelial atherosclerotic lesions and, therefore, endothelial denudation, which results in the exposure of active TF to flowing blood, leads to thrombosis and its sequelae in atherosclerotic lesions.