Inflammatory responses have been shown to contribute significantly to the rejection of grafts in both allo- and xenotransplantation. In particular, they play a pivotal role in promoting endothelial activation, complement deposition, and thrombosis, thereby compromising the graft function. In this study, we investigated the molecular and functional properties of genetically modified porcine aortic endothelial cells (PAECs) that carry a knockout of α1,3-galactosyltransferase and express human CD46 and thrombomodulin (3GM) in xenogeneic and inflammatory environments. Transcriptomic profiling revealed that these genetic modifications effectively reduced the intrinsic inflammatory and procoagulant phenotype of 3GM PAECs. Under xenogeneic activation, 3GM PAECs also exhibited minimal cellular responses distinct from those of wild-type (WT) PAECs, along with robust protection from the activation of the complement and coagulation systems. However, under inflammatory conditions, 3GM and WT PAECs showed more aligned transcriptional and functional profiles characterized by pronounced upregulation of proinflammatory and prothrombotic pathways, increased complement deposition, and a shift toward a more procoagulant state. This loss of protection during inflammatory conditions was associated with the induction of inflammatory and procoagulant mediators, including PAI-1 and uPAR, despite stable transgene expression. Collectively, these insights enhance our understanding of the complex interplay between inflammation, complement, coagulation, and immune regulation in xenotransplantation. Our findings further emphasize the importance of incorporating both genetic and pharmacologic strategies targeting inflammatory pathways to enhance graft compatibility.
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