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

TY - JOUR

T1 - Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching

AU - Swiatlowska, Pamela

AU - Sit, Brian

AU - Feng, Zhen

AU - Marhuenda, Emilie

AU - Xanthis, Ioannis

AU - Zingaro, Simona

AU - Ward, Matthew

AU - Zhou, Xinmiao

AU - Xiao, Qingzhong

AU - Shanahan, Cathy

AU - Jones, Gareth E

AU - Yu, Cheng-Han

AU - Iskratsch, Thomas

N1 - 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.

PY - 2022/4/15

Y1 - 2022/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85128475266&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abm3471

DO - 10.1126/sciadv.abm3471

M3 - Article

C2 - 35427166

SN - 2375-2548

VL - 8

SP - eabm3471

JO - Science Advances

JF - Science Advances

IS - 15

M1 - eabm3471

ER -