The Cardiovascular Benefit of Menopausal Hormone Treatment is Age-Dependent in Ldlr −/− Mice
Year: 2026
Type: preprint
Abstract: Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases in women after menopause, coinciding with declining estrogen levels. However, menopausal hormone therapy (MHT) has not consistently reduced ASCVD events in post-menopausal women, despite improvements in lipid profiles. The mechanisms underlying the diminished cardiovascular protective effects of estrogens during MHT remain poorly understood. Methods Atherosclerosis was established in 11-month-old female Ldlr −/− mice through Western diet feeding. To investigate the effects of menopause and 17β-estradiol (E 2 ) treatment on atherosclerotic burden during lipid normalization, mice were switched to a chow diet and subjected to ovariectomy (OVX) with and without E 2 treatment. To determine the contribution of inflammation to ASCVD risk during MHT, a cohort of mice received Ifnγ −/− bone marrow transplantation ( Ifnγ −/− BM ) before hormone treatment. To assess the influence of age on ASCVD risk during MHT, parallel studies were conducted in young mice, beginning at 12 weeks of age. Outcomes included lipid profiles, HDL function, circulating cytokines, atherosclerotic burden, liver lipid metabolic pathways and transcriptomic profiles, and hepatic estrogen receptor signaling. Results OVX increased atherosclerotic burden compared with sham-operation. E 2 treatment following OVX failed to reduce atherosclerosis in older mice but reduced atherosclerosis in young mice during chow diet-induced lipid normalization. In older mice, E 2 treatment elevated circulating IFNγ, impaired HDL antioxidant and cholesterol efflux functions, and increased plaque inflammation and features of plaque vulnerability. Suppression of inflammation through Ifnγ −/− BM transplantation restored HDL function and the ability of E 2 treatment to reduce atherosclerosis in older mice. In contrast, E 2 treatment following OVX in young mice limited inflammation and improved HDL function. E 2 treatment increased liver fatty acid metabolic signaling in both older and young mice but increased liver 4-hydroxynonenal (4-HNE) levels only in older mice. The age-dependent response was associated with remodeling of hepatic estrogen receptor (ER) expression, characterized by reduced ERα and increased G protein-coupled ER expression with aging. Liver transcriptomic analyses identified inflammatory and interferon-associated signatures following OVX+E 2 treatment in older mice. qPCR analyses across older and young mice suggested age-associated differences in inflammatory transcripts in response to E 2 . Conclusions These findings suggest that aging alters hepatic responses to E 2 treatment following ovariectomy, promoting oxidative stress and inflammatory signaling that contribute to persistent systemic inflammation and compromise the ability of E 2 to reduce atherosclerosis.
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Vanderbilt University, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1149166549, G1331566780, G1805704937, G3204331232, Vanderbilt Mouse Metabolic Phenotyping Center, G4784588152, G67822945, G7642566612, Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk, G8159288582, G879352401, G9000002043, G9000052735, Molecular and Cellular Basis for Digestive Diseases, Sex-Specific Risk of Metabolic and Cardiovascular Disease, Vanderbilt Diabetes Research Center, Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy?
OpenAlex ID: W7166877945