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

女性偏向的血管平滑肌细胞基因调控网络预测MYH9作为纤维斑块表型的调节因子

R Perry, Graham Lenert, Ernest Benavente, Aydin Bölük, Rebecca Hernandez, Lijiang Ma, Nicolas Barbera, Kelsey Watts, Victor Mendoza, Tiit Örd, Mari Taipale, Nadja Sachs, Jessica Pauli, Michal Mokry, Dominique de Kleijn, Menno de Winther, Manuel Mayr, Lars Maegdefessel, Karen Reue, Minna Kaikkonen, Johan Björkegren, Hester den Ruijter, Mete Civelek (2026) Female-Biased VSMC GRNs Predict MYH9 as Regulator of Fibrous Plaque Phenotype. Circ Res (IF: 16.2) 1 区

Abstract

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 females 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.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.Two female-biased vascular smooth muscle cell networks, GRNfloralwhite and GRNyellowgreen, were enriched for inflammatory and actin remodeling pathways, respectively. Single-cell RNA-sequencing confirmed sex-specific network activity in plaque vascular smooth muscle cells. Subcellular phenotyping identified a sex-specific gene expression program within GRNyellowgreen enriched for contractile and vascular development pathways. Bayesian network modeling identified MYH9 (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.These findings identify MYH9 as a regulator of female-biased fibrous plaque biology and highlight the importance of sex-specific network regulation in atherosclerosis.

动脉粥样硬化是冠状动脉疾病的炎症驱动因素，其表现形式包括不稳定的粥样斑块和稳定的纤维斑块。尽管粥样斑块已被广泛研究，但纤维斑块，尤其是在50岁以下女性中，其侵蚀作用显著促进冠状动脉血栓形成，目前仍知之甚少。斑块生物学中性别差异的分子机制，包括血管平滑肌细胞的作用，尚未完全阐明。本研究利用从119名男性和32名女性心脏移植供体中分离培养的人类血管平滑肌细胞的RNA测序数据，构建了性别特异性基因调控网络（GRN）。网络保留性分析鉴定出女性偏向的GRN，并在来自人类颈动脉粥样硬化斑块的单细胞RNA测序数据集中对其进行了评估。本研究采用贝叶斯网络建模和蛋白质组学分析来识别和验证调控驱动因子。结果发现，两个偏向女性的血管平滑肌细胞网络GRNfloralwhite和GRNyellowgreen分别富集于炎症通路和肌动蛋白重塑通路。单细胞RNA测序证实了斑块血管平滑肌细胞中存在性别特异性的网络活性。亚细胞表型分析发现，GRNyellowgreen网络内存在一个性别特异性的基因表达程序，该程序富集于收缩和血管发育通路。贝叶斯网络建模鉴定出MYH9（肌球蛋白重链9）为关键驱动基因。与男性相比，女性颈动脉斑块中MYH9丰度升高与平滑肌细胞含量增加和脂质含量降低相关，这与纤维斑块的特征相符。蛋白质组学分析证实，MYH9在女性纤维斑块中表达上调，并与稳定斑块特征相关。这些发现表明MYH9是女性特有纤维斑块生物学的调节因子，并强调了性别特异性网络调控在动脉粥样硬化中的重要性。

Links

http://www.ncbi.nlm.nih.gov/pubmed/41983287
http://dx.doi.org/10.1161/CIRCRESAHA.125.326941

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