Abstract
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.
Highlights
We identify a critical role for autophagy in regulating vascular smooth muscle cells (VSMCs) death and endoplasmic reticulum stress–dependent inflammation with important consequences for aortic wall homeostasis and repair
The response of vascular smooth muscle cells (VSMCs) to injury is a major determinant of the development and progression of vascular diseases, including atherosclerosis, restenosis, and aneurysm.[1,2,3]
VSMCs play important roles in the pathophysiology of aortic aneurysm (AA), and recent studies suggested a role for some aspects of VSMC phenotypic switching in AA.[11,12]
Summary
The data that support the findings of this study are available from the corresponding authors on reasonable request. All experiments were performed according to the Home Office, UK regulations and approved by the local ethics committee. Myh11-CreERt2/Rosa26-Confetti males were subjected to 10 intraperitoneal injections of 1 mg tamoxifen over 2 weeks followed by at least 1-week washout. TaglnCre+ mice (Jax n°004746) and Atg5flox/flox mice (kindly provided by Noburu Mizushima, University of Tokyo13) were bred in house. TaglnCre+/Atg5flox/flox animals were used to assess the role of autophagy in VSMC. Infusion of 1μg/(min·kg) Ang II, with or without treatment with 10 mg/kg anti-TGF (transforming growth factor) β (clone 1.D.11, BioXCell) was used to induce dissecting AA. Animals were analyzed as described in the online-only Data Supplement
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