Transplant vasculopathy is still a major obstacle to long-term graft survival. Pharmacological strategies aiming at preventing it are still lacking. Herein we show that the occurrence of transplant vasculopathy crucially depends on oxidative stress formation during organ recovery.

A fully MHC mismatched (BALB/c to C57BL/6) mouse aortic transplantation model was used. Before organ recovery donor animals received either saline (group I – IV) or 50mg/kg b.w. tetrahydrobiopterin i.m. (group V – VIII). Aortic grafts were analysed at 4 different time points: (a) immediately following recovery (group I + V), (b) following 24 hours cold ischemia time (CIT; group II + VI), (c) following 24 hours CIT and 45 min anastomosis time (group III + VII), (d) following 4 weeks graft reperfusion (group IV + VIII). Aortic tetrahydrobiopterin tissue levels were analysed by HPLC, oxidised proteins were measured by the Oxyblot procedure. Transplant vasculopathy was diagnosed by histopathology and immunohistochemistry.

24 hours CIT and 45 min anastomosis time resulted in strong neointima formation and α-smooth muscle actin expression, which could be prevented by donor pre-treatment with tetrahydrobiopterin (p = 0.008 and p = 0.01, respectively). Similarly, endothelial expression of P-selectin was significantly decreased in the pre-treatment group (p=0.01). Interestingly, grafts from pre-treated donor mice showed significantly less oxidised proteins than non-treated grafts at the time of organ recovery and following 24 hours CIT, but not at later time points (p = 0.003, p = 0.02 and p = ns, respectively).

These data point towards an important role of oxidative stress already during organ recovery, probably initiating chronic inflammation, which ends in chronic rejection. Analysing the protective mechanism of tetrahydrobiopterin might unravel attractive strategies to minimise transplant vasculopathy following organ transplantation.

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