McNeill M C, Li Mow Chee F, Ebrahimighaei R, Sala-Newby G B, Newby A C, Hathway T, Annaiah A S, Joseph S, Carrabba M, Bond M
Department of Translational Health Sciences, Bristol Medical School, Bristol BS2 8HW, United Kingdom.
Bristol Heart Institute, University Hospital, Bristol NHS Foundation Trust, Bristol BS2 8HW, United Kingdom.
J Mol Cell Cardiol. 2024 Feb;187:65-79. doi: 10.1016/j.yjmcc.2023.12.005. Epub 2024 Jan 5.
Vascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) are not fully understood.
Using hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo, we investigated the role of substrate stiffness in the regulation of VSMC calcification.
We demonstrate that increased substrate stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of substrate stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft substrate, elevated levels of nuclear actin monomer repress osteogenic differentiation and calcification by repressing YAP-mediated activation of both TEA Domain transcription factor (TEAD) and RUNX Family Transcription factor 2 (RUNX2).
This work highlights for the first time the role of nuclear actin in mediating substrate stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes.
血管钙化（VC）是不良心血管事件的常见独立危险因素，与糖尿病、高血压、慢性肾脏病和动脉粥样硬化相关。然而，调节血管平滑肌细胞（VSMC）成骨分化的机制尚未完全明确。
利用具有可调硬度的水凝胶以及赖氨酰氧化酶介导的人隐静脉体外硬化，我们研究了底物硬度在调节VSMC钙化中的作用。
我们证明，底物硬度增加会增强VSMC成骨分化和VSMC钙化。我们表明，底物硬度的影响是通过细胞核内肌动蛋白单体水平的降低介导的。我们表明，在与软底物相互作用的细胞中，核肌动蛋白单体水平升高通过抑制YAP介导的TEA结构域转录因子（TEAD）和RUNX家族转录因子2（RUNX2）的激活来抑制成骨分化和钙化。
这项工作首次突出了核肌动蛋白在介导底物硬度依赖性VSMC钙化中的作用以及YAP-TEAD和YAP-RUNX2转录复合物的双重作用。
