通过干细胞外泌体输送NAMPT在维持腹主动脉瘤平滑肌细胞表型稳态中的作用及机制

腹主动脉瘤AAA的病生机制为衰老过程中血管平滑肌细胞VSMC由收缩型向分泌型的过度转变，目前尚无特效干预措施。三元复合物MYOCD/SRF/CArG决定VSMC的表型转变，但调控机制未明。我们预实验发现转录因子FOXO4对其发挥着调节作用，而FOXO4又受长寿蛋白SIRT1的调控。烟酰胺腺嘌呤二核苷酸NAMPT可通过增强SIRT1的作用而延缓衰老，其主要存在于外泌体中。我们前期制备了富含NAMPT的干细胞外泌体，发现其可显著延缓VSMC的衰老。因此可以假说：SIRT1通过FOXO4调控VSMC的表型转变；富含NAMPT外泌体可通过增强SIRT1作用而延缓AAA血管壁的扩张成瘤进程。本课题拟以VSMC的表型转变和衰老为切入点，从NAMPT外泌体、SIRT1-FOXO4信号通路与细胞表型维持等多个层次，通过体内外实验全面探讨NAMPT对AAA的防治作用。研究结果具有重要的科学意义和应用潜力。

The pathogenesis of abdominal aortic aneurysm (AAA) is the excessive transition of vascular smooth muscle cells (VSMCs) from contractile types to secretory types during the aging. There is no useful treatments for AAA. The ternary complex MYOCD/SRF/CArG determines the phenotypic transformation of VSMCs. However, the possible mechanism remains unclear. Our preliminary experiments have showed that the forkhead transcription factor O4 (FOXO4) plays a regulatory role on MYOCD/SRF/CArG, and FOXO4 is regulated by the longevity protein SIRT1. Nicotinamide adenine dinucleotide (NAMPT) was reported to delay the aging and enhance the effects of SIRT1. We have successfully prepared mesenchymal stem cells with over-expression of NAMPT and isolated their exosomes, which was found to delay the senescence of VSMCs. Therefore, we hypothesized that SIRT1 regulates the phenotypic transformation of VSMCs through FOXO4; NAMPT-exosomes delay the aging process of AAA by enhancing the effect of SIRT1. This project aims to explore the prevention and treatment of NAMPT delivered in MSC-exosomes on AAA through in vivo and in vitro experiments from the multiple levels of NAMPT exosomes, SIRT1-FOXO4 signaling pathways and cell phenotype maintenance based on the aging and phenotype of VSMCs. Our study has important scientific significance and application potential on AAA treatment.