Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development.
Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development.
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DOI：
10.1161/circulationaha.114.012377
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发表时间：
2015-05-19
期刊：
影响因子：
37.8
通讯作者：
Tsao PS
中科院分区：
文献类型：
--
作者：
Raaz U;Zöllner AM;Schellinger IN;Toh R;Nakagami F;Brandt M;Emrich FC;Kayama Y;Eken S;Adam M;Maegdefessel L;Hertel T;Deng A;Jagger A;Buerke M;Dalman RL;Spin JM;Kuhl E;Tsao PS
主动脉壁硬化是一种在年龄和腹主动脉瘤 (AAA) 中持续观察到的现象。然而，其在 AAA 病理生理学中的作用很大程度上尚不明确。使用已建立的小鼠弹性蛋白酶诱导的 AAA 模型，我们证明节段性主动脉硬化 (SAS) 先于动脉瘤生长。有限元分析 (FEA) 表明，容易发生动脉瘤的主动脉段的早期硬化会导致相邻、更顺应的壁段的循环（收缩）束缚产生轴向（纵向）壁应力。 AAA 相邻主动脉段的介入性硬化（通过外部应用手术粘合剂）可显着减少动脉瘤的生长。这些变化与易发生 AAA 的主动脉节段硬度降低（由于相邻节段的硬度均衡）、轴向壁应力减少、活性氧 (ROS) 产生减少、弹性蛋白分解减弱、炎性细胞因子表达和巨噬细胞浸润减少以及主动脉壁内细胞凋亡减弱相关。离体节段性硬化主动脉节段的循环加压增加了与炎症和细胞外基质（ECM）重塑相关的基因的表达。最后，人体超声研究表明，衰老是 AAA 的一个重要危险因素，它伴随着节段性肾下主动脉硬化。本研究介绍了节段性主动脉硬化（SAS）的新概念，作为产生主动脉壁应力并引发动脉瘤生长的早期病理机制，从而描绘了潜在的潜在分子机制和治疗靶点。此外，监测 SAS 可能有助于识别有 AAA 风险的患者。
Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening (SAS) precedes aneurysm growth. Finite element analysis (FEA) reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with reduced segmental stiffness of the AAA-prone aorta (due to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species (ROS), attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, as well as attenuated apoptosis within the aortic wall. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix (ECM) remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. The present study introduces the novel concept of segmental aortic stiffening (SAS) as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring SAS may aid the identification of patients at risk for AAA.