Scientists show that vessel cells in atherosclerosis change specialization differently in males and females

Vessel cells change their 'profession' in atherosclerosis

Endothelial cells — the thin layer lining the inside of blood vessels — change their specialization in atherosclerosis, and in male and female mice this remodeling follows different scenarios. Cardiologists from Chongqing University and Shanghai Jiao Tong University came to this conclusion; the work was published in the journal Communications Biology.

How the experiment was conducted

The researchers tagged the endothelial cells of mice with a fluorescent marker and put atherosclerosis-prone animals on a fatty diet so that plaques would grow in their arteries. After 12 weeks, the team read the gene activity of every cell in the aortas and traced the fate of the marker: about a quarter of the tagged cells changed their profile, turning into smooth muscle cell-like cells, fibroblasts (connective tissue cells), fat cells, and even immune macrophages.

Sex differences and the role of hormones

The differences between the sexes showed up both in the scale of the remodeling and in its direction. In females, 24.8% of the descendants of the tagged cells lost their specialization, in males — 18.6%. In females, descendants resembling smooth muscle cells and fibroblasts were more common, while in males, macrophage-like cells that support inflammation prevailed. The smooth muscle pathway matters practically: such cells build the fibrous 'cap' of the plaque, which is usually thicker in women and makes the plaque more stable.

Hormones and molecular switches

The different cellular scenarios align with a clinical picture familiar to doctors: women develop overt atherosclerosis later than men, but after menopause, when estrogen levels fall, their risk quickly catches up with men's. The role of hormones was confirmed by a group of ovariectomized females — a model of menopause: the proportion of fat cells in their vessel walls more than doubled. The switch genes that determine cell fate were tested by the authors in computational models and on human cells in vitro: the protein KLF2 restrains the transformation of the endothelium, while CREB5 pushes it toward the smooth muscle pathway. The researchers call these molecules candidate targets for future drugs.

Limitations and significance of the work

The mechanisms of atherosclerosis have mostly been studied in males, and only in recent years have the European Society of Cardiology and the American Heart Association begun to require accounting for sex separately in research. For now, the conclusions have been drawn only in mice, and cells with a 'foreign' specialization in plaques are states with a certain set of genes rather than fully fledged mature cells, so a therapy tailored to a patient's sex is still far off. Earlier, biologists found out why female skin heals wounds faster than male skin.

Why this matters

The work shows that sex influences the cellular mechanisms of atherosclerosis, not only its clinical course: in males, endothelial remodeling leads to inflammatory macrophage-like cells, while in females it leads to a more stable fibrous 'cap' of the plaque. This primarily concerns patients with cardiovascular risk, especially women after menopause, in whom, according to the study, the proportion of fat cells in the vessels rose sharply. A practical implication is the targets KLF2 and CREB5 identified by the authors, which could underpin future drugs, although a therapy tailored by sex is still a long way off.