从滋养血管成熟化探讨四妙勇安汤稳定动脉粥样硬化斑块的机制

The rupture of unstable plaque has become the chief cause of severe cardio-cerebrovascular events，the angiogenesis of vasa vasorum in outer membrane is the main cause of unstable plaque. Promoting the mature of vasa vasorum and regulating the reconstruction of vasa vasorum network is a new method to stabilze the plaque. Hypoxia and inflammatory signaling activate PI3K/Akt-HIF-1α and VEGF-Ang1/Tie cascade signal chain, this process is the mainly mechanism of angiogenesis generate-mature. Preliminary studies show that SiMiaoYongAn had exact effect to stabilize atherosclerotic plaque. This study further regulates cell migration and vasa vasorum generate-mature through the experiments in vivo and in vitro for the targeted goals of vascular physical framework, which will illuminate the molecular mechanism of SiMiaoYongAn on the atherosclerotic plaque stabilization through the regulation of PI3K/Akt-HIF-1α and VEGF-Ang1/Tie cascade signal chain to modulate the reconstruction of vasa vasorum network and promote vascular normal metastasis.

不稳定的AS斑块破裂是发生重大心脑血管事件的罪魁祸首，新生的外膜滋养血管是斑块不稳定的主要原因。促进滋养血管的成熟化、调节滋养血管网重建，是稳定AS斑块的新途径。缺氧及炎症信号激活细胞内PI3K/Akt-HIF-1α及VEGF-Ang1/Tie级联反应链，是血管新生-成熟过程的主要调节机制。前期工作表明，四妙勇安汤具有稳定AS斑块的肯定效应。本研究进一步采用在体与离体实验相结合的方法，以血管物理构架为靶向目标，从调控细胞迁移及滋养血管新生-成熟的角度，阐释四妙勇安汤干预PI3K/Akt-HIF-1α及VEGF-Ang1/Tie级联信号链，调节滋养血管网重建，促进血管正常代谢，稳定AS斑块的分子生物学机制。

传统观点认为动脉粥样硬化是起始于各种原因导致的内皮细胞损伤，通过释放粘附因子，吸引单核细胞粘附浸润到内膜下吞噬脂质，同时血管平滑肌细胞增殖、迁移及形成新生内膜。但目前越来越多的证据表明血管外膜作为反应的先导者早期激活，从外向内参与了这一过程。新生的外膜滋养血管（Vasa Vasorum，VV）是斑块不稳定的主要原因，斑块内新生VV具有结构缺陷，与斑块内出血、斑块破裂及临床心脑血管事件的发生密切相关。因此，本研究以血管外膜VV为切入点，从多方面进行进行研究。采用添加1.1% L-蛋氨酸的高脂饲料喂养ApoE-/-小鼠8周，从病理形态学变化、病变成分转化、胶原构成和分布角度，观察血管外膜VV新生和成熟化在粥样硬化早期形成和发展过程中的作用，以临床确有疗效的四妙勇安汤进行干预，从脂代谢、病理形态学角度探讨四妙勇安汤干预外膜VV的效应机制；进而从调控HIF-1α-Apelin/APJ信号通路、Wnt/β-catenin信号通路，抑制VV新生；通过调节 Ang-1/Tie信号通路、Dll4tch11/VEGF信号通路，影响周细胞在VV外周的包绕、募集，促进VV成熟化，促进滋养血管网重建，改善其功能，进而稳定易损斑块。