Endothelial dysfunction and denudation in rat aortic allografts

Clinical evidence suggests that early endothelial cell (EC) dysfunction may predict the development of graft vascular disease. We wished to assess the early functional and morphological changes in the graft endothelium in a c ommonly used animal model of graft vascular disease, the rat aortic interpo sition allograft model. To assess graft EC function, regulation of vascular tone by ECs was monitored in aortic rings from grafts harvested at various times after transplantation (Tx), EC morphology was assessed by silver sta ining, which was followed by en face inspection of the luminal side of the grafts. Acetylcholine-induced EC-dependent vasorelaxation was reduced in al lografts at post-Tx days 7 and 14, whereas in syngeneic grafts EC-dependent relaxation was unaffected at any time after Tx. In separate grafts collect ed at the same time points, massive leukocyte adhesion at post-Tx day 7 and EC denudation at days 14 and 28 were evident in allografts but not in syng eneic grafts. At post-Tx day 56 (a time at which vessel wall remodeling is pronounced in this model), an intact EC layer covered the grafts. EC dysfun ction and morphological changes were prevented by immunosuppression of reci pient rats with cyclosporine. Our study shows that Tx-induced EC dysfunctio n in rat aortic allografts can be observed within 1 week of Tx in rat aorti c allografts and that this is occurring concomitantly with enhanced leukocy te adhesion to the graft ECs. These changes occur before any other morpholo gical or functional changes described thus far in this model and appear to be immune-driven. Taken together, these results show that Tx-induced early EC dysfunction, as described in patients, may be studied in the mode! of ra t aortic Tx.