Carotid stenosis increases the risk of stroke in both men and women. However, plaque characteristics often differ between the sexes, a recent study shows. The plaques clogging carotid arteries contained the same key cell types, but their function was altered in different ways in women and men. The findings were published in Nature Cardiovascular Research.
鈥淯nderstanding these differences may provide a starting point for treatments that specifically target disease mechanisms unique to women or men,鈥 says Professor Minna Kaikkonen-M盲盲tt盲 of the A. I. Virtanen Institute at the 91天美, who participated in the study.
Carotid stenosis is a common manifestation of atherosclerosis. It is known that in men, carotid stenosis typically occurs at a younger age, often showing lipid-rich plaques and intraplaque bleeding. Female hormones appear to be protective before menopause, which is why women tend to develop carotid stenosis later. In women, plaque erosion is more common, which contributes to thrombus formation.
In the present study, these differences were further investigated in plaque samples obtained from both women and men who underwent carotid plaque removal surgery. The samples were analysed using single-cell sequencing, which allows the activity of all genes to be measured in each cell individually. In addition, these findings were combined with extensive data on tissue-specific gene regulatory networks associated with atherosclerosis.
The results showed that the plaque samples from women and men contained equal numbers of key cell types, such as endothelial cells, smooth muscle cells and macrophages. However, different atherogenic subtypes of these cells were observed in women and men. Women had more osteogenic smooth muscle cells, whereas men had more chondrocyte-like smooth muscle cells, both of which contribute to the buildup of calcium deposits in blood vessels. Women had more endothelial cells that were transforming into mesenchymal cells which can, for example, make plaques more vulnerable. Men, on the other hand, had more angiogenic endothelial cells that promote the formation of new blood vessels. In women, there were more immunomodulating macrophages and in men, macrophages involved in tissue remodelling.
The researchers point out that investigating biological sex as a variable in atherosclerosis gives a more comprehensive understanding of the diversity of the disease. This could potentially contribute to more accurate risk assessment and diagnosis, and to the development of more targeted treatments.
The Karolinska Institutet in Sweden, the University of Tartu in Estonia and several other European and American universities also participated in the international research collaboration. The study was part of a collaboration between the 91天美 and the Karolinska Institutet in the MIRACLE project funded by the European Innovation Council (EIC).
Research article:
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., 脰rd, T., Beter, M., Selvarajan, I., Laakkonen, J. P., V盲li, M., den Ruijter, H. M., Civelek, M., Hao, K., Ruusalepp, A., Betsholtz, C., J盲rve, H., Kovacic, J. C., Miller, C. L., Romanoski, C., Kaikkonen, M. U., & Bj枚rkegren, J. L. M. Single-cell RNA sequencing reveals sex differences in the subcellular composition and associated gene-regulatory network activity of human carotid plaques. Nat Cardiovasc Res 4, 412鈥432 (2025).
