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Cited by 73Atherosclerosis and Cardiovascular DiseasesCellular Mechanics and InteractionsNitric Oxide and Endothelin Effects

Piezo1-Mediated Mechanotransduction Contributes to Disturbed Flow-Induced Atherosclerotic Endothelial Inflammation

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Lan, Yining, Lu, Jing, Zhang, Shaohan, Jie, Chunxiao, Chen, Chunyong, Xiao, Chao, Qin, Chao, Cheng, Daobin·2024·Journal of the American Heart Association
DOI 10.1161/jaha.123.035558PMC PMC11935715
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Abstract

Background Disturbed flow generates oscillatory shear stress (OSS), which in turn leads to endothelial inflammation and atherosclerosis. Piezo1, a biomechanical force sensor, plays a crucial role in the cardiovascular system. However, the specific role of Piezo1 in atherosclerosis remains to be fully elucidated. Methods and Results We detected the expression of Piezo1 in atherosclerotic mice and endothelial cells from regions with disturbed blood flow. The pharmacological inhibitor Piezo1 inhibitor (GsMTx4) was used to evaluate the impact of Piezo1 on plaque progression and endothelial inflammation. We examined Piezo1's direct response to OSS in vitro and its effects on endothelial inflammation. Furthermore, mechanistic studies were conducted to explore the potential molecular cascade through which Piezo1 mediates endothelial inflammation in response to OSS. Our findings revealed the upregulation of Piezo1 in apoE−/− (apolipoprotein E) atherosclerotic mice, which is associated with disturbed flow. Treatment with GsMTx4 not only delayed plaque progression but also mitigated endothelial inflammation in both chronic and disturbed flow‐induced atherosclerosis. Piezo1 was shown to facilitate calcium ions (Ca 2 + ) influx in response to OSS, thereby activating endothelial inflammation. This inflammatory response was attenuated in the absence of Piezo1. Additionally, we identified that under OSS, Piezo1 activates the Ca 2 + /CaM/CaMKII (calmodulin/calmodulin‐dependent protein kinases Ⅱ) pathways, which subsequently stimulate downstream kinases FAK (focal adhesion kinase) and Src. This leads to the activation of the OSS‐sensitive YAP (yes‐associated protein), ultimately triggering endothelial inflammation. Conclusions Our study highlights the key role of Piezo1 in atherosclerotic endothelial inflammation, proposing the Piezo1–Ca 2+ /CaM/CaMKII‐FAK/Src‐YAP axis as a previously unknown endothelial mechanotransduction pathway. Piezo1 is expected to become a potential therapeutic target for atherosclerosis and cardiovascular diseases.

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  • Upon mechanical activation, Piezo1 mediates Ca2+ influx, which can promote FAK phosphorylation via Ca2+-dependent mechanisms (e.g., calmodulin/CaMKII-mediated regulation) in other cell types.

    “Upon mechanical activation, Piezo1 mediates Ca2+ influx, which can promote FAK phosphorylation via Ca2+-dependent mechanisms (e.g., calmodulin/CaMKII-mediated regulation), as reported in other cell types.99,100”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [100]

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Authors
Lan, Y., Lu, J., Zhang, S., Jie, C., Chen, C., Xiao, C., Qin, C., & Cheng, D.
Affiliations
  • First Affiliated Hospital of GuangXi Medical University (CN)
  • Qiqihar Medical University (CN)
  • Liuzhou General Hospital (CN)
  • The First Affiliated Hospital of Guangxi Medical University
Corresponding author
  • Lan, Yining
  • Lu, Jing
  • Zhang, Shaohan
  • Qin, Chao
ORCID
Venue
Journal of the American Heart Association
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2024-11-05
Volume
13
Issue
21
Pages
e035558-e035558
ISSN
2047-9980 (ISSN-L)
DOI
10.1161/jaha.123.035558
PMC
PMC11935715
OpenAlex
W4403770360
Cited by
73
References
2
Citations by year
2026: 47 · 2025: 26
FWCI
12.21
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of the American Heart Association (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
Piezo1, mechanotransduction, flow disturbance, oscillatory shear stress, atherosclerosis, endothelial inflammation, GsMTx4, calcium influx, calmodulin, CaMKII, focal adhesion kinase, Src kinase, YAP, atherosclerotic plaque progression
MeSH terms
Mice, Knockout, ApoE, YAP-Signaling Proteins, Animals, Cells, Cultured, Disease Models, Animal, Humans, Inflammation, Ion Channels, Male, Mice, Inbred C57BL, Regional Blood Flow, Spider Venoms, Stress, Mechanical, Calcium Signaling, Intercellular Signaling Peptides and Proteins, Mechanotransduction, Cellular, Endothelial Cells, Atherosclerosis, Mice, Focal Adhesion Kinase 1, Plaque, Atherosclerotic

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