Expression of Fas ligand in arteries of hypercholesterolemic rabbits accelerates atherosclerotic lesion formation

Fas ligand (FasL) is expressed by cells of the arterial wall and is present in human atherosclerotic lesions. However, the role of Fast in modifying t he initiation and progression of atherosclerosis is unclear. To investigate the role of arterial Fast expression in the development of atherosclerosis , we first established a model of primary lesion formation in rabbit caroti d arteries. In this model, infusion of adenoviral vectors into surgically i solated, nondenuded arteries of hypercholesterolemic rabbits leads to the f ormation of humanlike early atherosclerotic lesions. Expression of Fast in arterial endothelium in this model decreased T-cell infiltration and expres sion of vascular cell adhesion molecule-1 but did not affect expression of intercellular adhesion molecule-1. Intimal lesions grew more rapidly in Fas L-transduced arteries than in arteries transduced with a control adenovirus that did not express a transgene. Total intimal macrophage accumulation wa s increased in FasL-transduced arteries, however, the proportion of lesion area occupied by macrophages was not elevated. The accelerated lesion growt h was primarily due to the accumulation of intimal smooth muscle cells with a synthetic proliferative phenotype. There was no significant apoptosis in FasL-transduced or control arteries and no granulocytic infiltrates. Thus, the net result of elevated Fast expression is to accelerate atheroscleroti c lesion growth by increasing lesion cellularity. Vascular expression of Fa st may contribute to the progression of atherosclerosis.