腔内支架对B型主动脉夹层血管重塑的作用及miRNAs在血管重塑中的调控机制

Type B aortic dissection (TBAD) is a vascular emergency. It has been widely accepted to treat TBAD with thoracic endovascular aortic repair (TEVAR) by tubing stent grafts (TG) since decades ago. In recent years, tapered stent graft (TaG) has been introduced to treat TBAD. TaG aims to provide better aortic remodeling with less oversizing rate in its distal landing site. Several research questions arise: What’s the effects of radial forces to aortic remodeling? Will the constitution of matrix and alteration of phenotype of aortic vascular smooth muscle cells (VSMCs) be impact by different radial forces? What’s the potential mechanisms of radial-force–directed aortic remodeling? Our previous study used volumetric measurement to delineate aortic remodeling process, and found that approximate one third of TBAD patients treated with TEVAR developed aortic aneurysmal degeneration during long-term follow-up. Metalloproteinase-9 (MMP-9) is well known to be involved in vast aortic pathogenesis. Our collaborative research team from the University of Hong Kong discovered that reduced clearance of exogenous MMP-9 upon silencing of LRP1 in human VSMCs in their previous study. We hypothesize that aortic remodeling process is significantly affected by radial forces. We also hypothesize that series of miRNAs are involved in the regulation of VSMCs phenotype alteration, matrix protein expression and cell apoptosis, in responding to radial forces. This study aims to: 1) compare aortic remodeling between patients treated with TG and TaG; 2) illustrate effects of radial forces to aortic remodeling from histocytologial perspective; 3) study the mechanisms that regulate aortic remodeling induced by radial forces. This study will reveal the potential mechanisms of radial-force–directed aortic remodeling regulated by miRNA, and will provide clinicians with a novel insight to treat TBAD.

1999年筒型支架(TG)开始广泛用于治疗B型主动脉夹层(TBAD)。锥形支架(TaG)近年开始逐步运用于临床治疗TBAD。TaG的设计期望通过减少远端卯定区的径向力达到更佳的血管重塑。不同大小的径向力是否会导致血管壁结构和血管平滑肌细胞(VSMC)表型产生不同的变化?这些变化是通过什么样的机制调控?我们前期利用容积测量发现近1/3的术后患者会出现血管重塑不良。我们也发现了主动脉疾病患者血管壁中MMP-9的异常表达以及miRNA-205对MMP的调控作用。我们假设血管壁的重塑过程可能会应径向力的不同而改变,重塑可能会通过一系列miRNA调控血管壁VSMC表型转化、基质构成以及细胞凋亡等机制完成。本项目拟完成以下研究:1)比较TG与TaG的治疗效果;2)阐明不同径向力对血管壁重构的影响;3)研究血管壁重塑的分子调控机制。本研究将从miRNA调控层面揭示血管重塑机制的基础,为治疗提供新的思路。

主动脉夹层是血管外科最危重的主动脉急症之一，该病的死亡率高且预后差。覆膜支架血管腔内修复术（TEVAR）是治疗B型主动脉夹层（TBAD）的主要方法之一，支架带来的不同机械径向支撑力可能会导致主动脉壁产生一系列不同结局的重构。为了证明不同大小的径向力对血管重塑的影响及具体的机制，本研究经过回顾性临床实验研究比较了筒形支架（TG）与锥形支架组（TaG）的TBAD患者TEVAR术后的重塑差异，发现了TG治疗的患者支架远端真腔面积扩大率更显著，但TG与TaG在胸主动脉近端及腹主动脉段的重塑没有显著差别。我们进一步利用动物实验结合人主动脉平滑肌细胞（HASMCs）培养的方法探究不同径向力对血管壁重塑的影响以及寻找参与血管壁重塑调控的miRNAs。细胞实验和动物实验发现证实了力学与血管平滑肌细胞存在重塑的关联，周期性牵张力（CTS）能够显著的增加HASMCs中miR-187-3p的表达水平，CTS通过miR-187-3p调控HASMCs细胞生物学行为，促进HASMCs的增殖和迁移，并同时抑制HASMCs的凋亡，且其作用效果与CTS振幅有关，证明了一定范围内的牵张力对平滑肌细胞重塑是具有保护性的作用。本研究的结果有一定的临床应用前景，可以指导临床医生为病人选择合适的支架尺寸与放大率。同时本研究也引出一个研究问题，我们推测一定范围内的力学形式，可以对主动脉壁重塑起到保护性的作用，而超出这个范围的某些力学形式可能会造成破坏性的作用。那么这个力学的范围和边界是什么呢？我们研究团队也将就这个研究问题与香港大学研究团队进一步合作，申请本年度的NSFC-RGC联合研究项目，将本研究的初步成果发扬光大，深入研究。