Background. Transplantation-induced systemic endothelial dysfunction causes severe cardiovascular morbidity and mortality after transplantation. Interventions that improve systemic endothelial function after transplantation and furthermore reduce intragraft vascular dysfunction might improve graft and patient survival. Treatment with the PPARγ agonist rosiglitazone is an intervention that potentially fulfills these criteria. In this study, we determined the effect of rosiglitazone treatment on transplantation-induced endothelial dysfunction and vasomotor activity in an experimental model for chronic transplant dysfunction in rats. Methods. Lewis abdominal aortic allografts were orthotopically transplanted into Brown Norway recipients that received either regular chow or chow containing rosiglitazone (∼4.2 mg/day). Endothelium-dependent (response to metacholine) and total (response to sodium nitrite) vasodilatory responses were determined in autologous thoracic aortic rings using an ex vivo organ bath setup. Measurements were performed 8 weeks after transplantation. Results. Aortic allografting induced systemic endothelial dysfunction as measured by reduced endothelium-dependent vasodilation in the recipient's vascular system. Rosiglitazone treatment restored endothelium-dependent vasodilatory responses to pretransplantation levels. However, rosiglitazone treatment reduced the total dilatory response despite normalized endothelial function, indicating impairment of vascular smooth muscle cell vasomotor activity. Conclusions. Rosiglitazone treatment after allogeneic transplantation restores endothelial function but impairs vascular smooth muscle cell vasomotor activity. This dichotomous effect of rosiglitazone might impede use of rosiglitazone after organ transplantation since this potentially increases cardiovascular risk despite improved endothelial cell function. Copyright

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Department of Internal Medicine

Onuta, G., Hillebrands, J.-L., Rienstra, S. A., Walther Boer, M., Klatter, F., Navis, G., … Roks, A. (2008). Dichotomous effects of rosiglitazone in transplantation-induced systemic vasodilator dysfunction in rats. Transplantation, 85(4), 582–588. doi:10.1097/TP.0b013e3181639c83