News Release

Chinese vascular surgery clinicians discovered that dysregulated YAP signaling promotes aortic dissection formation

Peer-Reviewed Publication

Higher Education Press

Figure 1


Downregulated RhoA/ROCK1/YAP/F-actin axis leads to decreased AoSMC stiffness and promotes AD formation.

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Credit: Wei Zhang, Mengxiao Wang, Enci Wang, Wei Lu, Zengxia Li, Yuchong Zhang, Gaofei Hu, Qi Zhang, Wenxin Shan, Yongjun Dang, Zhe Zhao, Lemin Zheng, Weiguo Fu, Lixin Wang

Aortic dissection (AD) is a fatal disease resulting from the dysfunction of elastin contractile units, which are composed of extracellular matrix (ECM) and aortic smooth muscle cells (AoSMCs), and eventual disruption of aortic integrity. AoSMCs are the center of the elastin contractile unit, and their phenotype and functionality can be affected by factors that predispose patients to AD, such as atherosclerosis, hypertension, smoking, hyperlipidemia, diabetes, and genetics. Augmented intrinsic AoSMC stiffness is reported as an adaptive change in aortas with aging and hypertension to prevent aortic diseases. However, the alteration of intrinsic AoSMC stiffness is in AD aortas and its correlation with AD occurrence has not been directly investigated.

To explore the variation of intrinsic AoSMC stiffness in AD aortas, primary AoSMCs isolated from corresponding segments in healthy and AD aortas were measured using aortic force microscopy. Intrinsic AoSMC stiffness was found to be decreased in AD aortas compared to healthy aortas, along with impaired F-actin polymerization. Based on the evidence that RhoA/ROCK1/YAP signaling was downregulated in AD aortas, we manipulated the signaling pathway to investigate its relationship with intrinsic AoSMC stiffness. Inhibition of RhoA activity by Rhosin or ROCK1 activity by Y27632 led to F-actin impairment and decreased intrinsic AoSMC stiffness. Depletion of YAP also resulted in impaired F-actin and reduced cell stiffness in AoSMCs. Moreover, the production of collagen I and III, two main ECM components in the vascular wall, was reduced in AoSMC with inhibition of the RhoA/ROCK1/YAP signaling pathway.

The role of intrinsic AoSMC stiffness was further investigated in an AD mouse model induced by β-aminopropionitrile (BAPN). The ROCK1 inhibitor Fasudil facilitated AD formation when co-administered with BAPN, suggesting that downregulation of the RhoA/ROCK1/YAP/F-actin signaling pathway and decreased AoSMC stiffness can promote AD formation. Increased phosphorylation of YAP, elastic fragmentation, and reduced collagen deposition were observed in the aortas of mice treated with BAPN and Fasudil. RNA sequencing further revealed downregulation in cAMP response element binding, actin filament organization, ECM organization, and collagen formation in the aortas of mice treated with BAPN and Fasudil compared to the control group.

In summary, the study unveils a downregulated RhoA/ROCK1/YAP/F-actin cascade with decreased intrinsic AoSMC stiffness in AD aortas, leading to increased elastin fragmentation and deficient collagen production, thereby promoting AD formation (Figure 1). This research underscores the critical role of AoSMC stiffness in maintaining aortic integrity and highlights potential targets to prevent AD occurrence. Moreover, the alterations in intrinsic AoSMC stiffness during AD formation also hint that the impact of cardiovascular medicine on AoSMC stiffness should be considered to prevent further collapse of aortic integrity.

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