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Spatial transcriptomics reveals a key role of fibroblast-like vascular smooth muscle cells in human atherosclerotic cell crosstalk and stability

Goncalves, Isabel LU orcid ; Pan, Mengyu LU orcid ; Singh, Pratibha LU ; Wang, Wenqi LU ; Zhao, Jing ; Dib, Lea ; Sundius, Lena LU ; Persson, Ana LU ; Gialeli, Chrysostomi LU and Fountas, Panagiotis LU , et al. (2026) In European Heart Journal p.1-22
Abstract

BACKGROUND AND AIMS: Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events.

METHODS: Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses.... (More)

BACKGROUND AND AIMS: Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events.

METHODS: Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing.

RESULTS: A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro.

CONCLUSIONS: This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
European Heart Journal
article number
ehaf1091
pages
1 - 22
publisher
Oxford University Press
external identifiers
  • pmid:41685669
ISSN
1522-9645
DOI
10.1093/eurheartj/ehaf1091
language
English
LU publication?
yes
additional info
© The Author(s) 2026. Published by Oxford University Press on behalf of the European Society of Cardiology.
id
5ac1fb99-3b1d-492c-80c1-91a527ebfaba
date added to LUP
2026-02-18 16:07:40
date last changed
2026-02-19 06:46:33
@article{5ac1fb99-3b1d-492c-80c1-91a527ebfaba,
  abstract     = {{<p>BACKGROUND AND AIMS: Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events.</p><p>METHODS: Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing.</p><p>RESULTS: A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro.</p><p>CONCLUSIONS: This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies.</p>}},
  author       = {{Goncalves, Isabel and Pan, Mengyu and Singh, Pratibha and Wang, Wenqi and Zhao, Jing and Dib, Lea and Sundius, Lena and Persson, Ana and Gialeli, Chrysostomi and Fountas, Panagiotis and Nitulescu, Mihaela and Nilsson, Jan and Malin, Stephen and Monaco, Claudia and Jørgensen, Helle F and Sun, Jiangming and Edsfeldt, Andreas}},
  issn         = {{1522-9645}},
  language     = {{eng}},
  month        = {{02}},
  pages        = {{1--22}},
  publisher    = {{Oxford University Press}},
  series       = {{European Heart Journal}},
  title        = {{Spatial transcriptomics reveals a key role of fibroblast-like vascular smooth muscle cells in human atherosclerotic cell crosstalk and stability}},
  url          = {{http://dx.doi.org/10.1093/eurheartj/ehaf1091}},
  doi          = {{10.1093/eurheartj/ehaf1091}},
  year         = {{2026}},
}