From the Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (M.C., J.C., J.R., F.L., A.L.T., A.F., J.H., M.R.B., H.F.J., Z.M.).
Clinical Chemistry Laboratory (J.R.), University Hospital of Nice, and Université Côte d'Azur, France.
Arterioscler Thromb Vasc Biol. 2019 Jun;39(6):1149-1159. doi: 10.1161/ATVBAHA.118.311727.
Objective- Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results- We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)-induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II-induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5. We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions- VSMCs undergo clonal expansion and phenotypic switching in Ang II-induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress-dependent inflammation with important consequences for aortic wall homeostasis and repair.
最近的研究表明，在主动脉瘤（AA）的发展过程中血管平滑肌细胞（VSMCs）发生表型转换。然而，谱系追踪研究仍然缺乏，并且对 VSMCs 在夹层 AA 形成过程中的行为知之甚少。
我们使用 VSMCs 的多色谱系追踪来追踪 Ang II（血管紧张素 II）诱导的夹层 AA 小鼠模型中损伤后它们的命运。我们还研究了自噬对 VSMC 对 AA 夹层反应的直接影响。最后，我们研究了这些过程与人类 AA 的相关性。在这里，我们显示出一部分中膜 VSMCs 经历克隆扩张，并且在 Ang II 诱导的夹层 AA 发展过程中，在假腔的外膜和边界处观察到 VSMC 生长。克隆扩张的 VSMCs 经历表型转换，VSMC 分化标志物下调和吞噬标志物上调，表明功能变化。特别是，自噬和内质网应激反应在受伤的 VSMCs 中被激活。通过删除自噬蛋白 5 基因（Atg5）在 VSMCs 中缺失自噬会增加 VSMC 死亡的易感性，增强内质网应激激活，并促进 IRE（肌醇需求酶）1α依赖性 VSMC 炎症。这些改变最终导致小鼠主动脉疾病的严重程度增加和致命性 AA 夹层的发生率增加。我们还报告了人类夹层 AA 中 VSMCs 中自噬和内质网应激标志物的表达增加。
在 Ang II 诱导的夹层 AA 中，VSMCs 经历克隆扩张和表型转换。我们还确定了自噬在调节 VSMC 死亡和内质网应激依赖性炎症中的关键作用，这对主动脉壁的动态平衡和修复具有重要意义。
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