Chen Jiani, Chu Yuan, Lan Yihui, Wan Jie, Zhang Yizhi, Liu Yuan, Yu Fan, Feng Lei, Zhu Yifei
Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China.
Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China.
Biochem Pharmacol. 2025 Oct;240:117107. doi: 10.1016/j.bcp.2025.117107. Epub 2025 Jul 5.
Early vascular lesions are closely associated with the phenotypic switching of vascular smooth muscle cells (VSMCs). Transient receptor potential vanilloid family member 4 (TRPV4) calcium channels are crucial for regulating vascular function. However, whether they contribute to the phenotypic switching of VSMCs remains unknown. Therefore, this study used a smooth muscle-specific TRPV4 knockout mouse model (TRPV4) to investigate the role of TRPV4 in phenotypic switching. Wire myography revealed significantly reduced phenylephrine/9,11-Methanoepoxy PGH2 vasoconstrictor response in the TRPV4 group compared to the control group. Furthermore, the TRPV4 mice had reduced contractile-related gene and protein expression in the aorta, suggesting the VSMCs lost their contractile phenotype. Carotid artery injury exacerbated pathological vascular remodelling in the smooth muscle and significantly increased neointima formation in the TRPV4 mice compared to the controls. In vitro experiments showed that VSMCs lacking TRPV4 had enhanced proliferation and migration. RNA sequencing demonstrated that the protein phosphatase 1 regulatory subunit 14a (CPI-17) is a pivotal regulator of VSMCs contraction and functionally associated with TRPV4-mediated vascular responses. Additionally, VSMCs exhibited similar phenotypes after silencing CPI-17 or TRPV4, indicating that they jointly regulate vasoconstriction. VSMCs overexpressing TRPV4 or CPI-17 had enhanced cell contraction, supporting our conclusion. Therefore, TRPV4 is a central coordinator of VSMC phenotypic homeostasis, and it maintains vascular homeostasis through molecular interactions with CPI-17 under physiological and injurious conditions. These results provide mechanistic insights into the vascular remodelling process and highlight potential therapeutic targets for vascular diseases characterised by phenotypic switching.
早期血管病变与血管平滑肌细胞（VSMC）的表型转换密切相关。瞬时受体电位香草酸家族成员4（TRPV4）钙通道对调节血管功能至关重要。然而，它们是否参与VSMC的表型转换尚不清楚。因此，本研究使用平滑肌特异性TRPV4基因敲除小鼠模型（TRPV4-/-）来研究TRPV4在表型转换中的作用。线肌张力测定显示，与对照组相比，TRPV4-/-组中去氧肾上腺素/9,11-甲撑环氧前列腺素H2血管收缩反应显著降低。此外，TRPV4-/-小鼠主动脉中收缩相关基因和蛋白表达降低，表明VSMC失去了收缩表型。与对照组相比，颈动脉损伤加剧了TRPV4-/-小鼠平滑肌的病理性血管重塑，并显著增加了新生内膜形成。体外实验表明，缺乏TRPV4的VSMC增殖和迁移增强。RNA测序表明，蛋白磷酸酶1调节亚基14a（CPI-17）是VSMC收缩的关键调节因子，并且在功能上与TRPV4介导的血管反应相关。此外，沉默CPI-17或TRPV4后，VSMC表现出相似的表型，表明它们共同调节血管收缩。过表达TRPV4或CPI-17的VSMC细胞收缩增强，支持了我们的结论。因此，TRPV4是VSMC表型稳态的核心协调者，在生理和损伤条件下，它通过与CPI-17的分子相互作用维持血管稳态。这些结果为血管重塑过程提供了机制性见解，并突出了以表型转换为特征的血管疾病的潜在治疗靶点。
