Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms

Apr 5, 2019Arteriosclerosis, thrombosis, and vascular biology

Changes in Blood Vessel Muscle Cells and Cell Recycling in Aortic Wall Tears

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Abstract

A subset of vascular smooth muscle cells (VSMCs) undergoes clonal expansion during the development of dissecting aortic aneurysms (AAs) in mice.

Clonal expansion of VSMCs is observed in the adventitia and borders of the false channel during Ang II-induced dissecting AAs.
VSMCs show phenotypic switching characterized by downregulation of differentiation markers and upregulation of phagocytic markers.
Autophagy and endoplasmic reticulum stress responses are activated in injured VSMCs.
Loss of autophagy in VSMCs increases susceptibility to cell death and enhances inflammation.
These changes lead to more severe aortic disease and a higher incidence of fatal AA dissection in mice lacking the autophagy gene Atg5.
Increased expression of autophagy and endoplasmic reticulum stress markers is found in VSMCs from human dissecting AAs.

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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.

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Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms

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