CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development.
CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development.
复制标题
DOI：
10.1172/jci.insight.162987
复制
发表时间：
2023-01-10
期刊：
影响因子：
8
通讯作者：
Lin, Zhiyong
中科院分区：
文献类型：
--
作者：
Wang, Yu;Liu, Xuesong;Xu, Qian;Xu, Wei;Zhou, Xianming;Leask, Andrew;Lin, Zhiyong
血管平滑肌细胞（SMC）表型转换被广泛认为是几种主动脉疾病（如主动脉瘤）发病的关键机制。细胞通信网络因子2 （CCN2）在人类病理和动物疾病模型中经常上调，发挥无数环境依赖的生物学功能。然而，目前对SMC- ccn2在SMC表型转换中的作用及其在腹主动脉瘤（AAA）病理中的功能的了解尚缺乏。在这里，我们发现SMC限制性CCN2缺乏导致血管紧张素ii注入（Ang ii注入）高胆固醇血症小鼠的肾下主动脉在与人类AAA相似的解剖位置发生AAA。值得注意的是，在SMC中沉默CCN2后，C57BL/6 WT小鼠对Ang ii诱导的AAA形成的抵抗丧失。此外，SMC-CCN2-KO小鼠的前aaa表型在不同的模型中重现，该模型涉及弹性酶- β-氨基丙腈的应用。在机制上，我们的研究结果表明CCN2与TGF-β信号通路相交并调节SMC标记物的表达。CCN2缺乏触发SMC重编程，与kr<s:1> ppel样因子4和收缩标记物表达的改变相关，这种重编程可能有助于小鼠AAA的发展。这些结果表明SMC- ccn2可能是SMC表型转换和AA生物学的新调节剂。
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.
登录
查看更多内容
影响因子：
37.8
作者：
Li Y;Ren P;Dawson A;Vasquez HG;Ageedi W;Zhang C;Luo W;Chen R;Li Y;Kim S;Lu HS;Cassis LA;Coselli JS;Daugherty A;Shen YH;LeMaire SA
通讯作者：
LeMaire SA
影响因子：
4.8
作者：
Duncan, MR;Frazier, KS;Grotendorst, GR
通讯作者：
Grotendorst, GR
影响因子：
4.8
作者：
Inoki, I;Shiomi, T;Okada, Y
通讯作者：
Okada, Y
影响因子：
5.4
作者：
Lindsay, Mark E.;Dietz, Harry C.
通讯作者：
Dietz, Harry C.
DOI：
10.1161/atvbaha.118.311727
发表时间：
2019-06-01
影响因子：
8.7
作者：
Clement, Marc;Chappell, Joel;Mallat, Ziad
通讯作者：
Mallat, Ziad