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CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development

Vascular smooth muscle cell (SMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases, such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exert...

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Autores principales: Wang, Yu, Liu, Xuesong, Xu, Qian, Xu, Wei, Zhou, Xianming, Leask, Andrew, Lin, Zhiyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870081/
https://www.ncbi.nlm.nih.gov/pubmed/36625347
http://dx.doi.org/10.1172/jci.insight.162987
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author Wang, Yu
Liu, Xuesong
Xu, Qian
Xu, Wei
Zhou, Xianming
Leask, Andrew
Lin, Zhiyong
author_facet Wang, Yu
Liu, Xuesong
Xu, Qian
Xu, Wei
Zhou, Xianming
Leask, Andrew
Lin, Zhiyong
author_sort Wang, Yu
collection PubMed
description Vascular smooth muscle cell (SMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases, such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts myriad context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here, we show that SMC-restricted CCN2 deficiency causes AAA in the infrarenal aorta of angiotensin II–infused (Ang II–infused) hypercholesterolemic mice at a similar anatomic location to human AAA. Notably, the resistance of naive C57BL/6 WT mice to Ang II–induced AAA formation is lost upon silencing of CCN2 in SMC. Furthermore, the pro-AAA phenotype of SMC-CCN2-KO mice is recapitulated in a different model that involves the application of elastase–β-aminopropionitrile. Mechanistically, our findings reveal that CCN2 intersects with TGF-β signaling and regulates SMC marker expression. Deficiency of CCN2 triggers SMC reprograming associated with alterations in Krüppel-like factor 4 and contractile marker expression, and this reprograming likely contributes to the development of AAA in mice. These results identify SMC-CCN2 as potentially a novel regulator of SMC phenotypic switching and AA biology.
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spelling pubmed-98700812023-02-06 CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development Wang, Yu Liu, Xuesong Xu, Qian Xu, Wei Zhou, Xianming Leask, Andrew Lin, Zhiyong JCI Insight Research Article Vascular smooth muscle cell (SMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases, such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts myriad context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here, we show that SMC-restricted CCN2 deficiency causes AAA in the infrarenal aorta of angiotensin II–infused (Ang II–infused) hypercholesterolemic mice at a similar anatomic location to human AAA. Notably, the resistance of naive C57BL/6 WT mice to Ang II–induced AAA formation is lost upon silencing of CCN2 in SMC. Furthermore, the pro-AAA phenotype of SMC-CCN2-KO mice is recapitulated in a different model that involves the application of elastase–β-aminopropionitrile. Mechanistically, our findings reveal that CCN2 intersects with TGF-β signaling and regulates SMC marker expression. Deficiency of CCN2 triggers SMC reprograming associated with alterations in Krüppel-like factor 4 and contractile marker expression, and this reprograming likely contributes to the development of AAA in mice. These results identify SMC-CCN2 as potentially a novel regulator of SMC phenotypic switching and AA biology. American Society for Clinical Investigation 2023-01-10 /pmc/articles/PMC9870081/ /pubmed/36625347 http://dx.doi.org/10.1172/jci.insight.162987 Text en © 2023 Wang et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Wang, Yu
Liu, Xuesong
Xu, Qian
Xu, Wei
Zhou, Xianming
Leask, Andrew
Lin, Zhiyong
CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
title CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
title_full CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
title_fullStr CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
title_full_unstemmed CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
title_short CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
title_sort ccn2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870081/
https://www.ncbi.nlm.nih.gov/pubmed/36625347
http://dx.doi.org/10.1172/jci.insight.162987
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