Vascular endothelial heterogeneity influences the outcome of pig-to-baboon cardiac and renal xenografts and the associated systemic manifestations

Aims: Molecular mechanisms underlying acute vascular rejection in pig-to-baboon xenotransplants and the associated thrombotic sequelae remain largely unknown. Qualitative differences of the vasculature of different organ grafts may dictate specific alterations in rejection response and any associated systemic manifestations. Methods: Baboons (n=27) received an immunosuppressive regimen, and underwent miniature swine or hDAF pig kidney (Group 1, n=6) or heart (Group 2, n=7) transplantation, or GalT-KO kidney transplantation (Group 3, n=14). A cDNA mini-array was developed to study expression of porcine pro-inflammatory, apoptosis-related, and vascular coagulant/fibrinolytic genes in these grafts. Data were validated at mRNA and protein levels. Results: Consumptive coagulopathy was seen in baboons transplanted with porcine kidneys (Group 1: 3 of 6), and (Group 3: 5 of 14) but less frequently following porcine cardiac transplantation (Group 2: 1 of 7). In renal xenografts (Group 1 and 3), upregulated genes included heme oxygenase-I and CD39, von Willebrand factor, P-selectin, and superoxide dismutases, irrespective of GalT status. In cardiac xenografts (Group 2), fibrin deposition and vascular injury were uniquely associated with the upregulation of the gene for plasminogen activator inhibitor-1. Conclusion: Differential responses of the vasculature with respect to regulation of clotting, platelet activation, and fibrinolysis may influence the development of thrombotic injury in porcine renal and cardiac xenografts. The proposal that disordered thromboregulation and abnormal fibrinolysis might occur in an organ-specific manner as components of graft rejection may be important for the generation of transgenic pigs for future clinical xenotransplantation.