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The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor β (TGF-β) signaling in smooth muscle. Here, we investigated the interactions between these different factors in aortic aneurysm development and identified a key role for smooth muscle cell (SMC) reprogramming into a mesenchymal stem cell (MSC)-like state. SMC-specific ablation of TGF-β signaling in Apoe-/- mice on a hypercholesterolemic diet led to development of aortic aneurysms exhibiting all the features of human disease, which was associated with transdifferentiation of a subset of contractile SMCs into an MSC-like intermediate state that generated osteoblasts, chondrocytes, adipocytes, and macrophages. This combination of medial SMC loss with marked increases in non-SMC aortic cell mass induced exuberant growth and dilation of the aorta, calcification and ossification of the aortic wall, and inflammation, resulting in aneurysm development. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Pei-Yu Chen, Lingfeng Qin, Guangxin Li, Jose Malagon-Lopez, Zheng Wang, Sonia Bergaya, Sharvari Gujja, Alexander W Caulk, Sae-Il Murtada, Xinbo Zhang, Zhen W Zhuang, Deepak A Rao, Guilin Wang, Zuzana Tobiasova, Bo Jiang, Ruth R Montgomery, Lele Sun, Hongye Sun, Edward A Fisher, Jeffrey R Gulcher, Carlos Fernandez-Hernando, Jay D Humphrey, George Tellides, Thomas W Chittenden, Michael Simons. Smooth Muscle Cell Reprogramming in Aortic Aneurysms. Cell stem cell. 2020 Apr 02;26(4):542-557.e11

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PMID: 32243809

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