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

• Type of Material: Article
• Authors: Yu Wang, Emory University; Xuesong Liu, Emory University; Qian Xu, Emory University; Wei Xu, Emory University; Xianming Zhou, Emory University; Zhiyong Lin, Emory University
• Language: English
• Date: 2023-01-10
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Wang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.162987
• Title of Journal or Parent Work: JCI Insight
• Volume: 8
• Issue: 1
• Grant/Funding Information: This work was supported by NIH grants 5R01HL144741 and 5R01HL152074, American Heart Association Transformative Project Award 20TPA35490431, and Emory University Startup Funds (all to ZL).
• Keywords: Extracellular matrix; Muscle, Smooth, Vascular; Mice; Animals; Myocytes, Smooth Muscle; Aortic Aneurysm, Abdominal; Cellular Reprogramming; Humans; Vascular Biology; Mice, Inbred C57BL
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery

Abstract

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.