Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention.

Background. Vascular pathologies constitute a major cause of graft rejection after organ transplantation. Recent studies have documented an improvement in transplant outcome when organs are preserved through pulsatile perfusion; however, the underlying mechanisms of these observations are poorly characterized. We hypothesized that the temporaryabsenceofflowoccurringinthecontextoforgancoldstorageconditionsdisruptsendothelialvasoprotective programs, and that this consequence of stasis may be a target for pharmacological modulation. Methods. The expression of the transcription factor Kruppel-like factor 2 (KLF2) and its vasoprotective target genes were assessed during cold storage conditions in cultured human endothelial cells and murine aortic segments. In addition, we evaluated the effect of simvastatin used as a supplement in a cold preservation solution on the expression of vasoprotective genes, and on endothelial activation and apoptosis. Results.TheexpressionofendothelialKLF2anditsvasoprotectivetranscriptionaltargetswererapidlylostduringcold preservation in vitro and ex vivo. Importantly, simvastatin treatment blocked the decay of KLF2, sustaining a vasoprotective phenotype, and preventing endothelial activation and apoptosis. Conclusions.Flowstasisleadstoacuteendothelialdysfunctionandapoptosisinthecontextofcoldstorageconditions. Supplementation of organ preservation solutions with pharmacologic agents that restore endothelial vasoprotective programs, by upregulating KLF2, may represent a significant advancement of current organ preservation techniques.