Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms
Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms
复制标题
主动脉夹层动脉瘤中血管平滑肌细胞的可塑性和自噬
DOI：
10.1161/atvbaha.118.311727
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发表时间：
2019-06-01
影响因子：
8.7
通讯作者：
Mallat, Ziad
中科院分区：
文献类型：
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作者：
Clement, Marc;Chappell, Joel;Mallat, Ziad
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，和解剖AA的形成过程中的VSMCs的行为知之甚少。方法和结果，我们使用血管紧张素II（血管紧张素II）诱导的解剖AA的小鼠模型中的血管平滑肌细胞损伤后，血管紧张素II（血管紧张素II）追踪其命运。我们还讨论了自噬对血管平滑肌细胞对AA解剖反应的直接影响。最后，我们研究了这些过程与人类AA的相关性。在这里，我们发现，一个子集的内侧VSMC进行克隆扩张，血管紧张素II诱导的发展过程中解剖AA的血管外膜和边界的假通道中观察到VSMC的副产物。克隆扩增的VSMC经历表型转换，VSMC分化标志物下调和吞噬标志物上调，指示功能变化。特别是，自噬和内质网应激反应在受损的VSMC中被激活。自噬蛋白5基因（Atg 5）缺失导致的VSMC自噬丧失增加了VSMC对死亡的易感性，增强了内质网应激激活，并促进了IRE（肌醇需要酶）1a依赖性VSMC炎症。这些变化最终导致主动脉疾病的严重程度增加，并在具有VSMC限制性Atg 5缺失的小鼠中发生致死性AA夹层。我们还报告增加表达的自噬和内质网应激标志物在人解剖AAS.Conclusions-VSMCs进行克隆扩张和表型转换在血管紧张素II诱导的解剖AAs在小鼠。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，这对主动脉壁的稳态和修复具有重要影响。
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) 1a-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.Visual Overview-An online visual overview is available for this article.