Sex Differences in Atherosclerosis Pathogenesis

Atherosclerosis develops through lipid accumulation, chronic inflammation and structural remodelling of the arterial wall, yet men and women differ markedly in disease onset, progression and outcomes. Until menopause, women are relatively protected, a benefit attributed largely to oestrogenic modulation of lipid metabolism, vasorelaxation, antioxidant defences and immune responses. After menopause, this protection wanes and cardiovascular risk converges with that of men. Beyond hormones, genetic sex—defined by XX or XY chromosome complement—influences lipid absorption, immune cell activation and vascular cell behaviour. In females, XX chromosomes promote differential expression of genes involved in lipoprotein uptake and inflammatory pathways, whereas XY complement may confer distinct mitochondrial and oxidative stress profiles. Interactions between sex hormones and chromosome complement shape plaque composition, stability and propensity to rupture, with practical implications for tailored prevention and therapy. Recognition of these sex-specific mechanisms has underpinned calls for sex-aware clinical trials and for the development of interventions that address both hormonal and chromosomal drivers of atherosclerotic disease.

Research from Nature Portfolio

Recent work using genetically modified mouse models has demonstrated that sex chromosome complement independently modulates atherogenesis. Mice bearing two X chromosomes, irrespective of gonadal sex, exhibit greater intestinal expression of lipid-processing enzymes and enhanced chylomicron assembly, leading to higher circulating pro-atherogenic lipids and accelerated plaque formation. This finding decouples the influence of sex chromosomes from that of oestrogens and androgens, providing a chromosomal basis for observed sex differences in plaque burden. By profiling both vascular lesions and lipid-metabolising tissues, this study highlights a primary role for X-linked gene dosage in dietary fat bioavailability and identifies novel targets for intervention beyond hormonal pathways.

Research from all publishers

An experimental comparison of gonadal sex and genetic sex in murine atherosclerosis has clarified the dual contributions of hormones and chromosomes. By exchanging gonads between XX and XY mice, researchers have shown that activation of the oestrogen receptor mitigates plaque development, while sex chromosome complement independently shapes lipid profiles, inflammatory cell recruitment and vascular remodelling. This work underscores the need to consider both hormonal milieu and chromosomal background when interpreting preclinical models and designing sex-specific therapies. In a complementary study in hyperlipidaemic rabbits, chronic infusion of urotensin II was found to exacerbate advanced lesions in both male and ovariectomised female animals. Urotensin II increased macrophage infiltration, intra-plaque neovascularisation and oxidative stress markers, while delaying lesion regression after lipid-lowering. These findings reveal how vasoactive peptides may interact with sex hormone depletion to destabilise plaques and suggest new avenues for targeting residual risk in postmenopausal atherosclerosis.

Sex Differences in Atherosclerosis Pathogenesis publication trend

The graph below shows the total number of articles in sex differences in atherosclerosis pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Atherosclerotic plaque: A complex lesion in the arterial intima composed of lipids, inflammatory cells, smooth muscle cells and fibrous elements, prone to rupture or erosion.

Endothelial-to-mesenchymal transition (EndMT): A process by which endothelial cells acquire mesenchymal characteristics, contributing to fibrosis and plaque instability.

Sex chromosome complement: The configuration of X and Y chromosomes (e.g. XX or XY) that influences gene expression beyond the effects of gonadal hormones.

Plaque regression: The reduction in lesion size or vulnerability following interventions such as lipid-lowering therapy, involving reduced inflammation and enhanced fibrous cap stability.

References

1. Gonadal sex vs genetic sex in experimental atherosclerosis. Atherosclerosis (2023).
2. Urotensin II Enhances Advanced Aortic Atherosclerosis Formation and Delays Plaque Regression in Hyperlipidemic Rabbits. International Journal of Molecular Sciences (2023).
3. XX sex chromosome complement promotes atherosclerosis in mice. Nature Communications (2019).