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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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Atherosclerosis was established in 11-month-old female\n                    <jats:italic>\n                      Ldlr\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice through Western diet feeding. To investigate the effects of menopause and 17\u03b2-estradiol (E\n                    <jats:sub>2<\/jats:sub>\n                    ) treatment on atherosclerotic burden during lipid normalization, mice were switched to a chow diet and subjected to ovariectomy (OVX) with and without E\n                    <jats:sub>2<\/jats:sub>\n                    treatment. To determine the contribution of inflammation to ASCVD risk during MHT, a cohort of mice received\n                    <jats:italic>\n                      Ifn\u03b3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    bone marrow transplantation (\n                    <jats:italic>\n                      Ifn\u03b3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>BM<\/jats:sup>\n                    <jats:italic>)<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    OVX increased atherosclerotic burden compared with sham-operation. E\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:sub>2<\/jats:sub>\n                    treatment elevated circulating IFN\u03b3, impaired HDL antioxidant and cholesterol efflux functions, and increased plaque inflammation and features of plaque vulnerability. Suppression of inflammation through\n                    <jats:italic>\n                      Ifn\u03b3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>BM<\/jats:sup>\n                    transplantation restored HDL function and the ability of E\n                    <jats:sub>2<\/jats:sub>\n                    treatment to reduce atherosclerosis in older mice. In contrast, E\n                    <jats:sub>2<\/jats:sub>\n                    treatment following OVX in young mice limited inflammation and improved HDL function. E\n                    <jats:sub>2<\/jats:sub>\n                    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 ER\u03b1 and increased G protein-coupled ER expression with aging. Liver transcriptomic analyses identified inflammatory and interferon-associated signatures following OVX+E\n                    <jats:sub>2<\/jats:sub>\n                    treatment in older mice. qPCR analyses across older and young mice suggested age-associated differences in inflammatory transcripts in response to E\n                    <jats:sub>2<\/jats:sub>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    These findings suggest that aging alters hepatic responses to E\n                    <jats:sub>2<\/jats:sub>\n                    treatment following ovariectomy, promoting oxidative stress and inflammatory signaling that contribute to persistent systemic inflammation and compromise the ability of E\n                    <jats:sub>2<\/jats:sub>\n                    to reduce atherosclerosis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.29.734522","type":"posted-content","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:10:27Z","timestamp":1782929427000},"source":"Crossref","is-referenced-by-count":0,"title":["The Cardiovascular Benefit of Menopausal Hormone Treatment is Age-Dependent in\n                  <i>\n                    Ldlr\n                    <sup>\u2212\/\u2212<\/sup>\n                  <\/i>\n                  Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0505-2499","authenticated-orcid":false,"given":"Cassandra D.","family":"Lalisan","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Gavin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, 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