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Initial apoptosis of smooth muscle cells in grafted vein is mediated by mechanically sensitive p53/insulin-like growth factor-1 receptor signaling pathway

【摘要】:正Objective On grafting a vein into an artery,the vein undergoes remodeling with an initial apoptosis of smooth muscle cells(SMCs),which is important for subsequent arterialization of the grafted vein.How- ever,the underlying mechanism of the apoptosis of SMCs in grafted veins is still unknown.Methods and Results We studied the apoptosis of SMCs in a mouse model of grafted vena cava onto carotid arteries.In the grafted veins,initial apoptosis of SMCs was at 12 h,which peaked at 3 days and declined at 4 weeks.The expression of p53 was high in the apoptotic SMCs of grafted veins.The role of p53 in apoptosis was then explored in mechanical stretch - treated SMCs cultured in 3 - D peptide gel.Increased expression of p53 in SMCs augmented the mechanical stretch - induced apoptosis,whereas knockout p53 in SMCs attenuated this effect.The expression of p53 was negatively related to the level of insulin - like growth factor - 1 receptor(IGF - 1R) in the grafted veins.The elevated expression of p53 in SMCs decreased the expression of IGF - 1R.Moreover, an increased expression of IGF - 1R prevented the mechanical stretch - induced apoptosis of SMCs.Finally, the expression of IGF - 1R was decreased in the apoptotic SMCs of grafted veins.Conclusion Our results demonstrate that level of p53 is a critical determinant for initial mechanical apoptosis of SMCs in grafted veins, and downregulation of IGF - 1R by p53 is responsible for mechanical stretch - induced apoptosis and vein graft remodeling.

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