Murine Model of Neointimal Formation and Stenosis in Vein Grafts

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Abstract
Objective— Previous studies have suggested that neointimal formation, a central cause of vein graft stenosis, has several potential cell sources. It was hypothesized that neointimal cells arise primarily from the cells of the vein graft. Methods and Results— This study investigated vein graft neointimal cell origins using a model of vein-to-artery cross-transplantation between transgenic Rosa26 mice (constitutive expression of bacterial β-galactosidase marker gene) and wild-type mice. Vein-originating cells survived and make a major contribution to neointimal formation within the vein graft, mostly adjacent to the lumen/endothelium, suggesting an intimate association with endothelial cells. Cross-transplantation of veins from thrombomodulin promoter-driven β-galactosidase reporter transgenic mice to wild-type arteries demonstrated survival of vein graft endothelial cells. Neointimal thickening was greater at the proximal and, to a lesser extent, distal ends, in comparison to the middle of the graft. By contrast, arterial grafts had almost no neointimal formation throughout the graft. The relative neointimal wall thickness is much greater in this model compared with other murine and larger-species vein graft models, even showing near-occlusive stenosis of the perianastomotic region. Conclusions— Vein graft neointimal cells arise predominantly from vein-derived cells, suggesting clinical relevance of stenosis-inhibiting therapies directed at the vein graft.