Virginia Tech scientists at the Fralin Biomedical Research Institute say the increased risk of cardiovascular disease after menopause may stem not only from declining hormone levels, but also from how those changes influence gene activity.

In a new paper published in the journal Cells, researchers examine growing evidence that declining estrogen levels can alter epigenetics, the system that controls when genes turn on and off. These changes may help explain why rates of heart disease, diabetes, and other metabolic conditions rise sharply in women after menopause.

In addition, the study identifies a potential link between estrogen loss, changes in gene regulation, and cardiovascular health. The epigenome, the full set of chemical modifications that regulate gene activity without altering DNA, has been studied extensively in breast cancer, but far less is known about how these mechanisms operate in the heart and cardiovascular system, according to Sumita Mishra, senior author of the study and assistant professor at the Fralin Biomedical Research Institute at VTC.

The findings suggest that estrogen-related gene regulation pathways, long studied in cancer biology, may also play an important role in cardiometabolic health. Heart disease is the leading cause of death for women, and risk increases during and after the menopause transition, according to the National Heart, Lung, and Blood Institute.

For years, we’ve focused on estrogen loss as the primary driver of increased heart disease risk after menopause. What’s becoming clear is that the story is more complex. By reframing menopause-related health risks around gene regulation, this work points to new directions for future treatments that may extend beyond hormone therapy to more directly target these regulatory pathways.”


 Sumita Mishra, senior author of the study and assistant professor, Fralin Biomedical Research Institute at VTC

In addition, genetic predisposition and environmental factors, such as diet, exercise, and metabolic disease, likely interact with these pathways to shape cardiovascular risk after menopause, beyond what hormone replacement alone can address.

Rather than identifying a single new mechanism, the results of the study offer a new way of understanding the problem by connecting hormone loss to longer-term changes in how the body regulates interconnected systems involved in cardiovascular and metabolic health.

The study also highlights that many existing interventions used to manage cardiometabolic disease in postmenopausal women, including lipid-lowering therapies, glucose-lowering agents such as GLP-1 receptor agonists and SGLT2 inhibitors, and lifestyle interventions such as diet and exercise, may intersect with gene regulatory pathways influenced by estrogen.

Emerging evidence suggests that these strategies can modulate metabolic and inflammatory signaling networks and, in some cases, the way DNA is packaged and regulated, helping to link current therapies to menopause-associated biological changes.

The researchers also highlight a gap in current knowledge, noting that much of the mechanistic evidence comes from laboratory and preclinical studies, and that more research in humans is needed to understand how these processes unfold over time.

Looking ahead, ongoing studies in the Mishra laboratory will focus on understanding how metabolic and gene-regulatory pathways are integrated in cardiometabolic disease, including in postmenopausal health. 

The new study also aligns with ongoing research in the Mishra laboratory focused on heart failure with preserved ejection fraction (HFpEF), a form of heart disease that disproportionately affects women and becomes more prevalent after menopause. HFpEF is closely linked to obesity and metabolic dysfunction and remains a major unmet clinical challenge.

In related work published in Hypertension, the Mishra team investigated how estrogen-dependent signaling pathways in the heart and vasculature are altered after menopause, contributing to changes in vascular function and metabolic regulation. 

Together, these findings emphasize a broader research focus on how hormonal signaling interacts with molecular pathways that govern cardiometabolic health in postmenopausal women. This growing body of work may help guide the development of more targeted strategies to prevent and treat cardiovascular disease in this population.

Mishra is a member of the Center for Exercise Medicine Research and the Center for Vascular and Heart Research at the Fralin Biomedical Research Institute. She is also an assistant professor in the Department of Human Nutrition, Foods, and Exercise in the Virginia Tech College of Agriculture and Life Sciences.

Source:

Journal reference:

Edwards, A., et al. (2026). Estrogen, Epigenetics, and Cardiometabolic Health: Mechanisms and Therapeutic Strategies in Postmenopausal Women. Cells. DOI: 10.3390/cells15060529. https://www.mdpi.com/2073-4409/15/6/529