C/EBPβ activation in vascular smooth muscle cells promotes hyperlipidemia-induced phenotypic transition and arterial stiffness

作者：Jun Ma, Xiangyu Yang, Yanan Li, Xin Zhang, Kai Liu, Yong Peng, Si Wang, Rufeng Shi, Xingwei Huo, Xueting Liu, Xinran Li, Runyu Ye, Zhipeng Zhang, Changqiang Yang, Lu Liu, Dan Gao, Shanshan Jia, Lirong Sun, Xianghao Zuo, Qingtao Meng, Xiaoping Chen · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02196-w · 被引用次数：8 · 研究领域：Cardiovascular Health and Disease Prevention、Atherosclerosis and Cardiovascular Diseases、Adipokines, Inflammation, and Metabolic Diseases

Abstract Arterial stiffness is a critical factor in cardiovascular and cerebrovascular events, yet clinical practice lacks specific therapeutic targets and biomarkers for its assessment. Hyperlipidemia closely correlates with arterial stiffness, and we observed elevated CCAAT/enhancer-binding protein β (C/EBPβ) expression in atherosclerotic mouse arterial walls. As the arterial medial layer predominantly consists of vascular smooth muscle cells (VSMCs), C/EBPβ‘s role in VSMCs under hyperlipidemia remains unclear. Our findings demonstrate that cholesterol-induced phenotypic transition of contractile VSMCs to macrophage-like cells coincides with C/EBPβ upregulation and activation. The activation of C/EBPβ is closely related to cellular assembly and organization, regulating the cytoskeleton via Disheveled-associated activator of morphogenesis 1 (Daam1). Conditional knockout of C/EBPβ in VSMCs of ApoE −/− mice alleviated hyperlipidemia-induced vascular remodeling and reduced the elevation of aortic pulse wave velocity. Additionally, C/EBPβ-regulated cytokine platelet-derived growth factor-CC (PDGF-CC) is correlated with brachial-ankle pulse wave velocity in humans. These results indicate that the activation of C/EBPβ promotes the transition of VSMCs from a contractile phenotype to a macrophage-like phenotype by regulating morphological changes, and C/EBPβ activation contributes to hyperlipidemia-induced arterial stiffness. PDGF-CC exhibited a significant association with arterial...