Zhu Mengmeng, Zhu Wenya, Pan Jianyuan, Chen Ziyi, Yan Yali, Wang Shengnan, Zhang Tingting, Yang Xiaoxiao, Xu Hongmei, Kong Xiangyong, Hu Hao, Xu Suowen, Zhang Xia, Zhang Buchun, Liao Chenzhong, Duan Yajun, Yang Shu, Chen Yuanli
Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Research (Wash D C). 2025 Aug 5;8:0815. doi: 10.34133/research.0815. eCollection 2025.
Phenotypic abnormalities in vascular smooth muscle cells (VSMCs) are believed to play essential roles in the progression of vascular diseases. Here, we explored the impact of fibroblast growth factor 21 (FGF21) on the phenotypic transition of VSMCs. Our findings revealed that FGF21 expression was substantially down-regulated in both human and mouse neointimal regions. Additionally, plasma FGF21 levels were lower in patients with atherosclerotic coronary artery disease (ASCAD) compared to those without ASCAD. Similarly, patients with restenosis exhibited reduced FGF21 levels compared to those without restenosis. In vivo, FGF21 deficiency accelerated intimal hyperplasia and decreased the number of contractile VSMCs in mouse neointima. However, hepatocyte-specific FGF21 knockout had no effect on ligation-induced intimal hyperplasia. Conversely, administration of recombinant FGF21 protein reduced neointima formation. This effect was abolished in mice with β-klotho VSMC-specific knockout, suggesting a direct effect of FGF21 on VSMCs. In vitro, FGF21 could promote the contractile phenotype transition of human aortic smooth muscle cells under basal or platelet-derived growth factor-BB incubation conditions. Furthermore, FGF21 activation led to the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which subsequently formed a complex with the serum response factor (SRF)-myocardin complex. This complex increased the phosphorylation of SRF at serine 224, thereby enhancing the transcription activation of the SRF-myocardin complex. Finally, we revealed that treatment with the FGF21 analog efruxifermin or activation of p38 MAPK using anisomycin effectively inhibited neointima formation. Taken together, these results indicate that modulating FGF21 or its subsequent signal pathways could serve as a therapeutic strategy for vascular diseases characterized by abnormal VSMC phenotypic transition.
血管平滑肌细胞（VSMCs）的表型异常被认为在血管疾病的进展中起重要作用。在此，我们探讨了成纤维细胞生长因子21（FGF21）对VSMCs表型转变的影响。我们的研究结果显示，FGF21在人和小鼠的新生内膜区域表达均显著下调。此外，与无动脉粥样硬化性冠状动脉疾病（ASCAD）的患者相比，ASCAD患者的血浆FGF21水平较低。同样，与无再狭窄的患者相比，再狭窄患者的FGF21水平降低。在体内，FGF21缺乏加速了小鼠新生内膜的内膜增生，并减少了收缩性VSMCs的数量。然而，肝细胞特异性FGF21基因敲除对结扎诱导的内膜增生没有影响。相反，给予重组FGF21蛋白可减少内膜形成。在β-klotho VSMC特异性基因敲除的小鼠中，这种作用被消除，表明FGF21对VSMCs有直接作用。在体外，FGF21可在基础或血小板衍生生长因子-BB孵育条件下促进人主动脉平滑肌细胞的收缩表型转变。此外，FGF21激活导致p38丝裂原活化蛋白激酶（p38 MAPK）磷酸化，随后与血清反应因子（SRF）-心肌素复合物形成复合物。该复合物增加了SRF丝氨酸224位点的磷酸化，从而增强了SRF-心肌素复合物的转录激活。最后，我们发现用FGF21类似物efruxifermin治疗或用茴香霉素激活p38 MAPK可有效抑制内膜形成。综上所述，这些结果表明，调节FGF21或其后续信号通路可作为以VSMC表型转变异常为特征的血管疾病的治疗策略。
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