Abstract 13774: Endothelial-Mesenchymal Transition Contributes to Neointimal Formation: an IGF-1 Receptor Mechanism Discovered in AV Graft
Arteriovenous (AV) access failure is a major cause of morbidity in ESRD patients. Failure is frequently accompanied by venous neoinitimal formation which progresses to occlusion of the access. Neointimal formation begins with loss of the endothelium followed by neointimal cell accumulation. At 24 hours after creating arteriovenous grafts in these mice, >90% endothelial cells in the vein segment disappeared. The endothelium was regenerated after 1 week. We found that some of the neointima cells are endothelial marker positive suggesting that EnMT (endothelial to mesenchymal cell transition) has occurred in the neointima. To pursue this hypothesis, we created AV grafts in transgenic mice, which the endothelial lineage cells are labeled with reporter gene LacZ. After 1 month, ~9% of X-Gal positive cells in the neointima co-stained with markers of mesenchymal cells and endothelial cells. In cultured endothelial cells, overexpression of the IGF-1 receptor (IGF-1R) or induction of IGF-1R by mechanical stretch increased EnMT, that associated with increased transcriptional repressors, Snail. Knockdown IGF-1R blocked stretch-induced EnMT. IGF-1R knockout reduced EnMT and neointimal formation in AV graft. In conclusion, we confirm that EnMT of endothelial cells contributes to the neointima of AV grafts. These results suggest potential therapeutic targets to treat AV graft occlusion.
- © 2013 by American Heart Association, Inc.