Endothelial mesenchymal transition as a driver of vascular graft calcification

Late calcification of vascular synthetic grafts is a recently underscored but not sufficiently investigated issue involving vascular substitutes. Most of the research in this field has been focused on material biocompatibility and development of strategies that allow an effective prosthetic incorporation into the recipient vascular tissues through neointima formation. In this short review we report the most generally accepted mechanisms leading to graft calcification with consequent detrimental effect on graft outcome. Besides to the role exerted by circulating or induced resident osteogenic progenitors, and by inflammatory cells, i.e. macrophages and multinuclear giant cells, endothelial cells are gaining attention as mediators of vascular diseases. Here we highlight the role of Endothelial-Mesenchymal Transition (End-MT), a process whereby endothelial cells acquire mesenchymal properties, in vascular calcification. End-MT has been observed in vascular graft, suggesting its involvement during remodelling response and calcification. We therefore tested this hypothesis by culturing an endothelial cell line (HUVEC) on poly-lactic-L-acid (PLLA) scaffolds under inflammatory milieu and investigating End-MT (SLUG, MMP-9, VIMENTIN) and osteogenic (BMP-2, ALP, RUNX-2) markers. Interestingly, HUVEC underwent an up-regulation of mesenchymal and osteogenic genes when in contact with PLLA, even in absence of inflammatory stimulation. As expected, the inflammatory cytokine combination (TNF-α + IL-1β) enhanced the End-MT and the osteogenic switch in HUVEC grown on PLLA. These preliminary data support a tight association between inflammation, calcification and polymer graft, also implicating a remodelling cell response to the biomaterial. Research in this direction needs to be improved, in the view of a future prevention strategy of vascular graft calcification and failure.