A reduction in the vascular smooth muscle cell focal adhesion component syndecan‐4 is associated with abdominal aortic aneurysm formation

• Published in: Clinical and translational medicine Vol. 11; no. 12; pp. e605 - n/a
• Main Authors: Hu, Jiaxin, Li, Yuyu, Wei, Zhonghai, Chen, Haiting, Sun, Xuan, Zhou, Qing, Zhang, Qi, Yin, Yong, Guo, Meng, Chen, Jianzhou, Zhai, Guangyao, Xu, Biao, Xie, Jun
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.12.2021; John Wiley and Sons Inc; Wiley
• Subjects: abdominal aortic aneurysm; Analysis of Variance; Animals; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - physiopathology; Aortic aneurysms; China; Disease Models, Animal; F/G‐actin‐MRTF‐A; Focal Adhesions - genetics; Focal Adhesions - metabolism; Mice; Mice, Inbred C57BL - abnormalities; Mice, Inbred C57BL - genetics; Muscle, Smooth, Vascular - abnormalities; Muscle, Smooth, Vascular - physiopathology; phenotypic change; RhoA; Smooth muscle; Syndecan-4 - analysis; Syndecan-4 - blood; Syndecan-4 - deficiency; syndecan‐4; China; F/G-actin-MRTF-A; phenotypic change; RhoA; abdominal aortic aneurysm; syndecan-4
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.605

Background Abdominal aortic aneurysm (AAA) is a serious vascular disease for which there is no effective drug treatment. The incidence of AAA increases significantly as a subject ages, and the molecular mechanism of AAA formation remains elusive. In the present study, we investigated the role of syndecan‐4 (SDC4), an important component of focal adhesions, in AAA formation and its association with phenotypic changes in vascular smooth muscle cells (VSMCs). Methods and results The protein expression levels of SDC4 were significantly decreased in human AAA tissue and those of an AAA mouse model. Moreover, SDC4 knockout (KO) in mice accelerated the formation and rupture of AAAs induced by angiotensin II (Ang II) and calcium chloride (CaCl2) Mechanistically, the decrease in SDC4 led to the transformation of cultured VSMCs from a contractile to a secretory phenotype. The RhoA‐F/G‐actin‐myocardin‐related transcription factor‐A (MRTF‐A) signalling pathway was shown to be involved in SDC4‐dependent VSMC alteration. Sphingosine‐1‐phosphate (S1P), a G‐protein‐coupled receptor, attenuated the AAA formation in SDC4‐KO and wild‐type (WT) mice in response to Ang II and CaCl2 stimulation. Conclusion We herein demonstrated that silencing SDC4 was associated with increased AAA formation and phenotypic changes in VSMCs via the RhoA‐F/G‐actin‐MRTF‐A pathway. These findings indicated that a reduction in SDC4 expression was an important pathological alteration and potential therapeutic target for AAA formation. 1. Downregulation of SDC4 was observed in human AAA sample and AAA animal model. 2. Loss of SDC4 promoted VSMC contractile phenotype alternation via RhoA‐F/G‐actin‐MRTFA pathway, which ultimately led to the formation of AAA. 3. CYM‐5478, a RhoA agonist, was used to successfully prevent AAA formation in the SDC4 KO and WT mice.