Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

Pamela Swiatlowska; William Tipping; Emilie Marhuenda; Paolo Severi; Vitalay Fomin; Zhisheng Yang; Qingzhong Xiao; Duncan Graham; Cathy Shanahan; Thomas Iskratsch

doi:10.1002/advs.202308686

Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

Pamela Swiatlowska, William Tipping, Emilie Marhuenda, Paolo Severi, Vitalay Fomin, Zhisheng Yang, Qingzhong Xiao, Duncan Graham, Cathy Shanahan, Thomas Iskratsch^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Arterial Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up >50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear. Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways. Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.

Original language	English
Journal	Advanced Science
DOIs	https://doi.org/10.1002/advs.202308686
Publication status	Accepted/In press - 2023

Keywords

atherosclerosis
foam cells
mechanosensing
pressure sensing
vascular smooth muscle cells

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10.1002/advs.202308686

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@article{305c9385f6e84c59a919477305e8d49a,

title = "Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells",

abstract = "Arterial Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up >50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear. Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways. Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.",

keywords = "atherosclerosis, foam cells, mechanosensing, pressure sensing, vascular smooth muscle cells",

author = "Pamela Swiatlowska and William Tipping and Emilie Marhuenda and Paolo Severi and Vitalay Fomin and Zhisheng Yang and Qingzhong Xiao and Duncan Graham and Cathy Shanahan and Thomas Iskratsch",

note = "Funding Information: The authors would like to acknowledge Giulia Mastroianni and the QMUL Transmission Electron Microscope Facility for the TEM imaging, Charles Cox for Piezo1 plasmids, Rebecca Oakey and Will Villiers for helpful discussions related to CUT&Tag analysis. : T.I. was supported by a British Heart Foundation project grant (grant no. PG/20/6/34 835) and a BBSRC new investigator award (grant no. BB/S001123/1). D.G was supported through the EPSRC project EP/N010914/1. Funding Publisher Copyright: {\textcopyright} 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.",

year = "2023",

doi = "10.1002/advs.202308686",

language = "English",

journal = "Advanced Science",

issn = "2198-3844",

publisher = "Wiley-VCH Verlag",

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TY - JOUR

T1 - Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

AU - Swiatlowska, Pamela

AU - Tipping, William

AU - Marhuenda, Emilie

AU - Severi, Paolo

AU - Fomin, Vitalay

AU - Yang, Zhisheng

AU - Xiao, Qingzhong

AU - Graham, Duncan

AU - Shanahan, Cathy

AU - Iskratsch, Thomas

N1 - Funding Information: The authors would like to acknowledge Giulia Mastroianni and the QMUL Transmission Electron Microscope Facility for the TEM imaging, Charles Cox for Piezo1 plasmids, Rebecca Oakey and Will Villiers for helpful discussions related to CUT&Tag analysis. : T.I. was supported by a British Heart Foundation project grant (grant no. PG/20/6/34 835) and a BBSRC new investigator award (grant no. BB/S001123/1). D.G was supported through the EPSRC project EP/N010914/1. Funding Publisher Copyright: © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

PY - 2023

Y1 - 2023

N2 - Arterial Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up >50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear. Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways. Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.

AB - Arterial Vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up >50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear. Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways. Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.

KW - atherosclerosis

KW - foam cells

KW - mechanosensing

KW - pressure sensing

KW - vascular smooth muscle cells

UR - http://www.scopus.com/inward/record.url?scp=85180506243&partnerID=8YFLogxK

U2 - 10.1002/advs.202308686

DO - 10.1002/advs.202308686

M3 - Article

AN - SCOPUS:85180506243

SN - 2198-3844

JO - Advanced Science

JF - Advanced Science

ER -

Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

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Keywords

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