Female-Biased VSMC GRNs Predict MYH9 as Regulator of Fibrous Plaque Phenotype

BACKGROUND: Atherosclerosis, an inflammatory driver of coronary artery disease, manifests as unstable atheromatous plaques and stable fibrous plaques. Although atheromatous plaques have been extensively studied, fibrous plaques, particularly in women aged <50 years, where erosion contributes significantly to coronary thrombosis, remain less understood. The molecular mechanisms underlying sex differences in plaque biology, including vascular smooth muscle cell contributions, are incompletely defined. METHODS: Sex-specific gene regulatory networks (GRNs) were constructed from RNA-sequencing data of cultured human vascular smooth muscle cells isolated from 119 male and 32 female heart transplant donors. Network preservation analyses identified female-biased GRNs, which were evaluated in single-cell RNA-sequencing data sets from human carotid atherosclerotic plaques. Bayesian network modeling and proteomic analyses were used to identify and validate regulatory drivers. RESULTS: (myosin heavy chain 9) as a key driver gene. Elevated MYH9 abundance was associated with increased smooth muscle cell content and reduced lipid content in female carotid plaques compared with males, consistent with fibrous plaque features. Proteomic analyses confirmed MYH9 upregulation in female fibrous plaques and association with stable plaque characteristics. CONCLUSIONS: These findings identify MYH9 as a regulator of female-biased fibrous plaque biology and highlight the importance of sex-specific network regulation in atherosclerosis.

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Publication Details

Journal
Circulation Research
Published
2026-04-15
DOI
https://doi.org/10.1161/circresaha.125.326941
Primary Topic
Protease and Inhibitor Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Female-Biased VSMC GRNs Predict MYH9 as Regulator of Fibrous Plaque Phenotype

Nicolas Barbera, K Reue, Nadja Sachs, Minna Unelma Kaikkonen et al.
Circulation Research
Protease and Inhibitor Mechanisms
article

Female-Biased VSMC GRNs Predict MYH9 as Regulator of Fibrous Plaque Phenotype

Nicolas Barbera, K Reue, Nadja Sachs, Minna Unelma Kaikkonen, Mari Taipale, Aydın Bölük, Lars Mäegdefessel, Tiit Örd, Mete Civelek, Menno P.J. de Winther, Ernest Diez Benavente, Kelsey Watts, Lijiang Ma, Hester M. den Ruijter, Jessica Pauli, Manuel Mayr, Graham Lenert, M Mokry, R. Noah Perry, Johan Bjorkegren, Dominique P.V. de Kleijn, Rebecca Hernandez, Victor Mendoza
article en

Abstract

BACKGROUND: Atherosclerosis, an inflammatory driver of coronary artery disease, manifests as unstable atheromatous plaques and stable fibrous plaques. Although atheromatous plaques have been extensively studied, fibrous plaques, particularly in women aged <50 years, where erosion contributes significantly to coronary thrombosis, remain less understood. The molecular mechanisms underlying sex differences in plaque biology, including vascular smooth muscle cell contributions, are incompletely defined. METHODS: Sex-specific gene regulatory networks (GRNs) were constructed from RNA-sequencing data of cultured human vascular smooth muscle cells isolated from 119 male and 32 female heart transplant donors. Network preservation analyses identified female-biased GRNs, which were evaluated in single-cell RNA-sequencing data sets from human carotid atherosclerotic plaques. Bayesian network modeling and proteomic analyses were used to identify and validate regulatory drivers. RESULTS: (myosin heavy chain 9) as a key driver gene. Elevated MYH9 abundance was associated with increased smooth muscle cell content and reduced lipid content in female carotid plaques compared with males, consistent with fibrous plaque features. Proteomic analyses confirmed MYH9 upregulation in female fibrous plaques and association with stable plaque characteristics. CONCLUSIONS: These findings identify MYH9 as a regulator of female-biased fibrous plaque biology and highlight the importance of sex-specific network regulation in atherosclerosis.

Circulation ResearchVol. 138(10)
Karolinska University Hospital (SE), University of California, Los Angeles (US), University of Eastern Finland (FI), Utrecht University (NL), TUM Klinikum (DE), Karolinska Institutet (SE), University Medical Center Utrecht (NL), Lung Institute (US), Precision for Medicine (United States) (US), Institute of Human Genetics (PL), German Centre for Cardiovascular Research (DE), Amsterdam University Medical Centers (NL), Clinical Gene Networks (Sweden) (SE), University of Virginia (US), Medical University of Vienna (AT), University of Amsterdam (NL), Icahn School of Medicine at Mount Sinai (US)
American Heart Association, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hjärt-Lungfonden, Vetenskapsrådet, National Institutes of Health, HORIZON EUROPE Framework Programme, HORIZON EUROPE European Innovation Council
Gender equality
Openalex Percentile: Top 23%
Protease and Inhibitor Mechanisms
DOIOpen Access PDFOpenAlex
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