Department of Vascular Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Department of Vascular and Endovascular Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
J Vasc Surg. 2018 Jun;67(6):1891-1900.e4. doi: 10.1016/j.jvs.2017.05.088. Epub 2017 Sep 11.
The processes driving human abdominal aortic aneurysm (AAA) progression are not fully understood. Although antiinflammatory and proteolytic strategies effectively quench aneurysm progression in preclinical models, so far all clinical interventions failed. These observations hint at an incomplete understanding of the processes involved in AAA progression and rupture. Interestingly, strong clinical and molecular associations exist between popliteal artery aneurysms (PAAs) and AAAs; however, PAAs have an extremely low propensity to rupture. We thus reasoned that differences between these aneurysms may provide clues toward (auxiliary) processes involved in AAA-related wall debilitation. A better understanding of the pathophysiologic processes driving AAA growth can contribute to pharmaceutical treatments in the future.
Aneurysmal wall samples were collected during open elective and emergency repair. Control perirenal aorta was obtained during kidney transplantation, and reference popliteal tissue obtained from the anatomy department. This study incorporates various techniques including (immuno)histochemistry, Western Blot, quantitative polymerase chain reaction, microarray, and cell culture.
Histologic evaluation of AAAs, PAAs, and control aorta shows extensive medial (PAA) and transmural fibrosis (AAA), and reveals abundant adventitial adipocytes aggregates as an exclusive phenomenon of AAAs (P < .001). Quantitative polymerase chain reaction, immunohistochemistry, Western blotting, and microarray analysis showed enrichment of adipogenic mediators (C/EBP family P = .027; KLF5 P < .000; and peroxisome proliferator activated receptor-γ, P = .032) in AAA tissue. In vitro differentiation tests indicated a sharply increased adipogenic potential of AAA adventitial mesenchymal cells (P < .0001). Observed enrichment of adipocyte-related genes and pathways in ruptured AAA (P < .0003) supports an association between the extent of fatty degeneration and rupture.
This translational study identifies extensive adventitial fatty degeneration as an ignored and distinctive feature of AAA disease. Enrichment of adipocyte genesis and adipocyte-related genes in ruptured AAA point to an association between the extent of fatty degeneration and rupture. This observation may (partly) explain the failure of medical therapy and could provide a lead for pharmaceutical alleviation of AAA progression.
导致人类腹主动脉瘤（AAA）进展的过程尚不完全清楚。尽管在临床前模型中，抗炎和蛋白水解策略能有效抑制动脉瘤的进展，但迄今为止所有的临床干预都失败了。这些观察结果表明，人们对 AAA 进展和破裂过程中涉及的过程还没有完全了解。有趣的是，在临床和分子上，腘动脉瘤（PAA）和 AAA 之间存在很强的关联性；然而，PAA 发生破裂的可能性极低。因此，我们推断这些动脉瘤之间的差异可能为 AAA 相关壁弱化过程中涉及的（辅助）过程提供线索。更好地了解推动 AAA 生长的病理生理过程，可以为未来的药物治疗做出贡献。
在开放性择期和急诊修复期间收集动脉瘤壁样本。在肾移植期间获得肾周对照主动脉，从解剖学系获得参考腘动脉组织。本研究结合了多种技术，包括（免疫）组织化学、Western Blot、定量聚合酶链反应、微阵列和细胞培养。
AAA、PAA 和对照主动脉的组织学评估显示，广泛的中层（PAA）和贯穿性纤维化（AAA），并揭示了丰富的外膜脂肪细胞聚集，这是 AAA 的一种独特现象（P<.001）。定量聚合酶链反应、免疫组织化学、Western blot 和微阵列分析显示，脂肪生成介质（C/EBP 家族 P=0.027；KLF5 P<.000；过氧化物酶体增殖物激活受体-γ P=0.032）在 AAA 组织中富集。体外分化试验表明，AAA 外膜间充质细胞的成脂潜能明显增加（P<.0001）。破裂的 AAA 中观察到脂肪细胞相关基因和途径的富集（P<.0003），支持脂肪变性程度与破裂之间的关联。
这项转化研究将广泛的外膜脂肪变性确定为 AAA 疾病中被忽视的独特特征。破裂的 AAA 中脂肪生成和脂肪细胞相关基因的富集表明，脂肪变性程度与破裂之间存在关联。这一观察结果可能（部分）解释了药物治疗失败的原因，并为药物缓解 AAA 进展提供了线索。
