Molecular regulation of endothelial cell activation: novel mechanisms and emerging targets

To outline some recently described mechanisms that regulate endothelial cell function and vascular inflammation. A particular focus will be given to protective or adverse regulatory events, at molecular or cellular level, that could provide new therapeutic targets to control endothelial cell dysfunction in the xenotransplantation setting.

Targeting protective gene expression to porcine endothelium by genetic modification of the donor is required to improve xenograft survival by controlling endothelial cell activation and death. Increasing evidences indicate the importance of microRNAs in the regulation of endothelial cell function and propose strategies to overcome endothelial cell activation, injury that may apply to xenotransplantation. Recent advances have been made in our understanding of endothelial cell repair, replacement and senescence that could impact on xenograft outcome. Finally, refinements to endothelial cell targeting in vivo also open the way to the design of effective gene transfer in vascularized organs.

Xenograft survival in the pig-to-primate experimental model is still limited by humoral vascular xenograft rejection resulting from acute endothelial cell damage. Current knowledge in mechanisms regulating inflammatory gene transcription in endothelial cell such as microRNAs, endothelial cell infection by virus, endothelial cell repair, senescence and replacement processes may help to design new approaches targeting and protecting graft endothelial cell to avoid vascular injury and rejection.