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

Research output: Contribution to journalArticlepeer-review

Pamela Swiatlowska, Brian Sit, Zhen Feng, Emilie Marhuenda, Ioannis Xanthis, Simona Zingaro, Matthew Ward, Xinmiao Zhou, Qingzhong Xiao, Cathy Shanahan, Gareth E Jones, Cheng-Han Yu, Thomas Iskratsch

Original languageEnglish
Article numbereabm3471
Pages (from-to)eabm3471
JournalScience Advances
Volume8
Issue number15
DOIs
Published15 Apr 2022

Bibliographical note

Funding Information: We would like to acknowledge funding from BBSRC BB/S001123/1 to T.I.; British Heart Foundation PG/20/6/34835 to T.I., C.S., and G.E.J.; RG/17/2/32808 to C.S.; and PG/15/11/31279 and PG/20/10458 to Q.X.; and Research Grant Council of Hong Kong GRF 17122019 to C.-h.Y. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

King's Authors

Abstract

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.

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