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Peer-reviewedCC BY-NC-NDJournal of Proteome Research

Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling

  • Kathrine V. Jokumsen1,2
  • Lasse G. Lorentzen3,1,2,4
  • Karin Yeung3,1,5,4
  • Timothy Andrew Resch3,1,5,4
  • Jonas Eiberg6,3,1,7,5,4
  • Michael J. Davies1,2
  • Luke F. Gamon8,1,2
8 affiliations
  1. 1University of Copenhagen , , ,
  2. 2Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark
  3. 3Copenhagen University Hospital - Rigshospitalet , , ,
  4. 4Department of Vascular Surgery, Heart Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
  5. 5Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  6. 6Capital Region of Denmark , , ,
  7. 7Copenhagen Academy for Medical Education and Simulation (CAMES), Capital Region of Denmark, Copenhagen, Denmark
  8. 8Lund University , , Clinical Research Centre , ,
Open at sourceDOICite

Abstract

Plaque heterogeneity underlies the propensity of atherosclerotic lesions to rupture and trigger cardiovascular events. Most proteomic studies examine bulk changes, obscuring key spatial differences in protein abundance. We report a high-resolution spatial proteomics workflow exploring the molecular landscape of human plaques and a murine myocardium. By combining laser capture microdissection with high-sensitivity ion-mobility mass spectrometry, spatial profiling of cellular and extracellular matrix (ECM) proteomes was achieved. Over 2700 proteins were detected from 50,000 μm2 areas, revealing substantial intraplaque heterogeneity across distinct regions (lipid-rich, media, shoulder, necrotic core, intima) and distance from the artery lumen. Inverse correlations between proteases (cathepsin B) and core structural ECM proteins (perlecan, HSPG2) indicated active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell–cell communication. Blood coagulation signatures, including platelet degranulation and fibrin formation, were enriched at the intima. Inflammatory (clusters of differentiation 4/68, CD4/CD68; vascular cell adhesion molecule 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intraplaque hemorrhage. This workflow resolves proteomic changes over ∼200 μm distances, providing unprecedented insights into plaque morphology and offers a powerful tool for elucidating plaque biology.

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Cite

BibTeXRIS
BibTeX
@article{jokumsen2026spatial,
  title = {{Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling}},
  author = {Kathrine V. Jokumsen and Lasse G. Lorentzen and Karin Yeung and Timothy Andrew Resch and Jonas Eiberg and Michael J. Davies and Luke F. Gamon},
  journal = {Journal of Proteome Research},
  year = {2026},
  month = aug,
  doi = {10.1021/acs.jproteome.6c00011},
  url = {https://doi.org/10.1021/acs.jproteome.6c00011},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling
AU  - Kathrine V. Jokumsen
AU  - Lasse G. Lorentzen
AU  - Karin Yeung
AU  - Timothy Andrew Resch
AU  - Jonas Eiberg
AU  - Michael J. Davies
AU  - Luke F. Gamon
PY  - 2026
DA  - 2026/08/19
JO  - Journal of Proteome Research
DO  - 10.1021/acs.jproteome.6c00011
UR  - https://doi.org/10.1021/acs.jproteome.6c00011
AB  - Plaque heterogeneity underlies the propensity of atherosclerotic lesions to rupture and trigger cardiovascular events. Most proteomic studies examine bulk changes, obscuring key spatial differences in protein abundance. We report a high-resolution spatial proteomics workflow exploring the molecular landscape of human plaques and a murine myocardium. By combining laser capture microdissection with high-sensitivity ion-mobility mass spectrometry, spatial profiling of cellular and extracellular matrix (ECM) proteomes was achieved. Over 2700 proteins were detected from 50,000 μm2 areas, revealing substantial intraplaque heterogeneity across distinct regions (lipid-rich, media, shoulder, necrotic core, intima) and distance from the artery lumen. Inverse correlations between proteases (cathepsin B) and core structural ECM proteins (perlecan, HSPG2) indicated active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell–cell communication. Blood coagulation signatures, including platelet degranulation and fibrin formation, were enriched at the intima. Inflammatory (clusters of differentiation 4/68, CD4/CD68; vascular cell adhesion molecule 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intraplaque hemorrhage. This workflow resolves proteomic changes over ∼200 μm distances, providing unprecedented insights into plaque morphology and offers a powerful tool for elucidating plaque biology.
SN  - 1535-3893
SN  - 1535-3907
ER  -