@article{Sakkers:2026:10.1161/CIRCRESAHA.125.327624,
author = {Sakkers, TR and Mili, E and Winter, H and Kapteijn, D and Perry, RN and Barbera, N and Watts, K and Dias, IR and Meteva, D and Wesseling, M and Mol, BM and de, Borst GJ and de, Kleijn DPV and van, der Laan SW and Civelek, M and White, SJ and Maegdefessel, L and Mayr, M and Pasterkamp, G and Mokry, M and Benavente, ED and den, Ruijter HM},
doi = {10.1161/CIRCRESAHA.125.327624},
journal = {Circ Res},
title = {Atherosclerotic Fibrous Plaques in Women Present ECM Remodeling Linked to TGF-β.},
url = {http://dx.doi.org/10.1161/CIRCRESAHA.125.327624},
year = {2026}
}

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TY  - JOUR
AB  - BACKGROUND: Sex and atherosclerotic plaque histology are intertwined, with fibrous plaques being more prevalent in women. Plaque erosion, a significant contributor to acute coronary syndromes, is linked to fibrous plaques and is more prevalent in women than men. We hypothesize that the molecular drivers of histologically determined fibrous plaques differ between men and women. METHODS: Human end-stage atherosclerotic plaques were isolated from carotid endarterectomy patients included in the Athero-Express Biobank. Fibrous plaques were histologically assessed, linked to clinical characteristics, and processed for protein, bulk RNA, single-cell RNA, and DNA methylation data. We leveraged sex-differential gene expression and deconvolution analyses to uncover sex-biased molecular and cellular mechanisms. Spatial transcriptomics localized gene expression patterns in plaques. Furthermore, we studied the female-biased processes in human plaque endothelial cells and vascular smooth muscle cells stimulated with TGF-β (transforming growth factor-β), with or without SMAD3 (SMAD family member 3) inhibition. RESULTS: Of 1889 atherosclerotic plaques (1309 male and 580 female), fibrous lesions were observed in 50% of female and 31% of male patients. Compared with patients with atheromatous plaques (n=494), women with fibrous plaques exhibited a high prevalence of smoking, while men with fibrous plaques presented more often with diabetes. Female fibrous plaques were characterized by smooth muscle cell-driven ECM (extracellular matrix) remodeling, TGF-β response, and endothelial-to-mesenchymal transition, localized to the fibrous cap. Conversely, male plaques were linked to macrophage-mediated inflammation proximal to the core, dependent on diabetes. Finally, we experimentally confirmed these female-biased mechanisms, showing that TGF-β induced endothelial-to-mesenchymal transition in endothelial cells and ECM remodeling in vascular smooth muscle cells, both part
AU  - Sakkers,TR
AU  - Mili,E
AU  - Winter,H
AU  - Kapteijn,D
AU  - Perry,RN
AU  - Barbera,N
AU  - Watts,K
AU  - Dias,IR
AU  - Meteva,D
AU  - Wesseling,M
AU  - Mol,BM
AU  - de,Borst GJ
AU  - de,Kleijn DPV
AU  - van,der Laan SW
AU  - Civelek,M
AU  - White,SJ
AU  - Maegdefessel,L
AU  - Mayr,M
AU  - Pasterkamp,G
AU  - Mokry,M
AU  - Benavente,ED
AU  - den,Ruijter HM
DO  - 10.1161/CIRCRESAHA.125.327624
PY  - 2026///
TI  - Atherosclerotic Fibrous Plaques in Women Present ECM Remodeling Linked to TGF-β.
T2  - Circ Res
UR  - http://dx.doi.org/10.1161/CIRCRESAHA.125.327624
UR  - https://www.ncbi.nlm.nih.gov/pubmed/41641539
ER  - 

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