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<p>Atherosclerotic plaque rupture is a major cause of cerebrovascular events, yet the molecular determinants underlying vulnerability-related plaque morphology, including fibrous-cap thickness, remain incompletely defined. Using histomorphology-guided spatial proteomics, here we delineate molecular programs associated with plaque cap phenotype across discrete plaque subregions. In 112 carotid endarterectomy specimens, differences between thin-cap and thick-cap plaques were predominantly localized to the necrotic core and fibrous cap. These differences were enriched for processes related to inflammation, lipid handling, extracellular matrix remodeling and ossification/calcification, and supported the presence of proteome-based plaque subtypes. PCSK9 was among the proteins most strongly associated with thin-cap plaques. Consistently, an in vitro model of necrotic core-like oxidative and inflammatory stress increased PCSK9 secretion in primary vascular smooth muscle cells. Together, these findings localize molecular programs associated with cap phenotype to plaque compartments and provide a framework for spatially informed biomarker discovery in advanced carotid atherosclerosis.</p>

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Proteomics reveals spatial and molecular heterogeneities in advanced atherosclerotic carotid artery plaques

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Ankit Sinha,
  • Nadja Sachs,
  • Elena Kratz,
  • Jessica Pauli,
  • Sophia Steigerwald,
  • Vincent Albrecht,
  • Thierry M. Nordmann,
  • Enes Ugur,
  • Edwin H. Rodriguez,
  • Marie-Luise Engl,
  • Patricia Skowronek,
  • Denys Oliinyk,
  • Andreas Metousis,
  • Moritz von Scheidt,
  • Michael Wierer,
  • Hanna Winter,
  • Heribert Schunkert,
  • Daniela Branzan,
  • Lars Maegdefessel,
  • Matthias Mann

摘要

Atherosclerotic plaque rupture is a major cause of cerebrovascular events, yet the molecular determinants underlying vulnerability-related plaque morphology, including fibrous-cap thickness, remain incompletely defined. Using histomorphology-guided spatial proteomics, here we delineate molecular programs associated with plaque cap phenotype across discrete plaque subregions. In 112 carotid endarterectomy specimens, differences between thin-cap and thick-cap plaques were predominantly localized to the necrotic core and fibrous cap. These differences were enriched for processes related to inflammation, lipid handling, extracellular matrix remodeling and ossification/calcification, and supported the presence of proteome-based plaque subtypes. PCSK9 was among the proteins most strongly associated with thin-cap plaques. Consistently, an in vitro model of necrotic core-like oxidative and inflammatory stress increased PCSK9 secretion in primary vascular smooth muscle cells. Together, these findings localize molecular programs associated with cap phenotype to plaque compartments and provide a framework for spatially informed biomarker discovery in advanced carotid atherosclerosis.