Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching

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 (hemodyn...

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Published in:Science advances 2022-04, Vol.8 (15), p.eabm3471-eabm3471
Main Authors: 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
Format: Article
Language:English
Subjects:
Atherosclerosis - pathology
Biomedicine and Life Sciences
Biophysics
Cell Biology
Cell Proliferation
Cells, Cultured
Humans
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Phenotype
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abm3471