Article Impact Level: HIGH Data Quality: STRONG Summary of Nature Cardiovascular Research, 4(4), 412–432. https://doi.org/10.1038/s44161-025-00628-y Dr. Katyayani Sukhavasi et al.
Points
- The study used deep single-cell RNA sequencing to analyze carotid plaques from 7,690 cells and identified sex-specific differences in subcellular composition, with notable variations between male and female patients.
- In females, carotid plaques showed a predominance of osteogenic smooth muscle cells, immunomodulating macrophages, and endothelial cells undergoing endothelial-to-mesenchymal transition. At the same time, males had chondrocytic smooth muscle cells and angiogenic endothelial cells.
- Bioinformatic analysis linked sex-biased differences to gene-regulatory networks, identifying GRN195 in male endothelial cells related to angiogenesis and GRN33 and GRN122 in female macrophages and endothelial cells.
- The study found that molecular processes underlying carotid stenosis may differ between sexes, influencing the progression and manifestation of atherosclerosis. This highlights the importance of sex-specific factors in cardiovascular diseases.
- Functional validation of GRN195’s impact on endothelial cell proliferation in males suggests that targeting sex-specific molecular mechanisms could improve personalized prevention and treatment strategies for cardiovascular diseases, enhancing outcomes for both sexes.
Summary
This study aimed to investigate sex-specific differences in the cellular and molecular characteristics of carotid plaques linked to ischemic stroke. Using deep single-cell RNA sequencing, the researchers analyzed 7,690 cells from carotid plaques of male and female patients. They found no significant sex differences in the major cell types, such as smooth muscle cells, macrophages, and endothelial cells. However, notable sex-biased differences were identified in the subcellular composition. In females, the plaques showed a predominance of osteogenic smooth muscle cells, immunomodulating macrophages (MPs), and endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition. In contrast, males exhibited smooth muscle cells with a chondrocytic phenotype, tissue remodeling MPs, and angiogenic ECs.
Subsequent bioinformatic analysis integrated these findings with gene-regulatory networks (GRNs) from the Stockholm–Tartu Atherosclerosis Reverse Network Engineering Task study. The study identified GRN195, related to angiogenesis and T cell-mediated cytotoxicity, in male ECs, while GRN33 and GRN122, associated with TREM2−/TREM1+ MPs and endothelial-to-mesenchymal transition, were found in females. These findings suggest that the molecular processes underlying carotid stenosis may differ between men and women, influencing the progression and manifestation of atherosclerosis.
The functional validation of GRN195’s impact on EC proliferation in males provided further evidence for sex-specific therapeutic targets in atherosclerosis. This study emphasizes the importance of considering biological sex in understanding carotid artery disease. It suggests that targeting sex-specific molecular mechanisms may improve personalized prevention and treatment strategies for cardiovascular diseases. Understanding these differences can lead to more effective interventions and outcomes for both men and women.
Link to the article: https://www.nature.com/articles/s44161-025-00628-y
References Sukhavasi, K., Mocci, G., Ma, L., Hodonsky, C. J., Diez Benevante, E., Muhl, L., Liu, J., Gustafsson, S., Buyandelger, B., Koplev, S., Lendahl, U., Vanlandewijck, M., Singha, P., Örd, T., Beter, M., Selvarajan, I., Laakkonen, J. P., Väli, M., Den Ruijter, H. M., … Björkegren, J. L. M. (2025). Single-cell RNA sequencing reveals sex differences in the subcellular composition and associated gene-regulatory network activity of human carotid plaques. Nature Cardiovascular Research, 4(4), 412–432. https://doi.org/10.1038/s44161-025-00628-y
