Swiatlowska Pamela, Sit Brian, Feng Zhen, Marhuenda Emilie, Xanthis Ioannis, Zingaro Simona, Ward Matthew, Zhou Xinmiao, Xiao Qingzhong, Shanahan Cathy, Jones Gareth E, Yu Cheng-Han, Iskratsch Thomas
School of Engineering and Materials Science, Queen Mary University of London, London, UK.
Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK.
Sci Adv. 2022 Apr 15;8(15):eabm3471. doi: 10.1126/sciadv.abm3471.
Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of their role as risk factors for atherosclerosis, we sought here to systematically study the impact of matrix stiffness and (hemodynamic) pressure on VSMCs. Thereby, we find that pressure and stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, leads to a full phenotypic switch including the formation of matrix-degrading podosomes. We further analyze the molecular mechanism in stiffness and pressure sensing and identify a regulation through different but overlapping pathways culminating in the regulation of the actin cytoskeleton through cofilin. Together, our data show how different pathological mechanical signals combined but through distinct pathways accelerate a phenotypic switch that will ultimately contribute to atherosclerotic disease progression.
血管平滑肌细胞（VSMCs）在动脉粥样硬化进展中起核心作用，在此过程中它们从收缩表型转变为合成表型。由于它们作为动脉粥样硬化风险因素的作用，我们在此旨在系统研究基质硬度和（血流动力学）压力对血管平滑肌细胞的影响。由此，我们发现压力和硬度分别影响血管平滑肌细胞表型。然而，只有高血压压力和基质顺应性的组合，以及动脉粥样硬化期间普遍存在的此类机械刺激，才会导致包括形成基质降解性足体在内的完全表型转换。我们进一步分析了硬度和压力感知中的分子机制，并确定通过不同但重叠的途径进行调节，最终通过丝切蛋白对肌动蛋白细胞骨架进行调节。总之，我们的数据表明不同的病理机械信号如何通过不同途径组合起来加速表型转换，并最终导致动脉粥样硬化疾病进展。
