{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:48:44Z","timestamp":1785743324770,"version":"3.56.0"},"reference-count":70,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23PRE1023169"],"award-info":[{"award-number":["23PRE1023169"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"\n Abstract<\/jats:title>\n \n The\n APOE\u03b54<\/jats:italic>\n allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between\n APOE<\/jats:italic>\n genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous\n APOE\u03b53<\/jats:italic>\n and\n APOE\u03b54<\/jats:italic>\n mice (\n n<\/jats:italic>\n \u00a0=\u00a019\u201320\/group; \u223c6\u00a0months old) that were fed a high\u2010fat diet and were ovariectomized (OVX), OVX and supplemented with 17\u03b2\u2010oestradiol, or left intact. In\n APOE\u03b53<\/jats:italic>\n mice, OVX was associated with impaired posterior cerebral artery endothelium\u2010dependent dilatation, which was rescued by 17\u03b2\u2010oestradiol. However, in\n APOE\u03b54<\/jats:italic>\n mice, there was no effect of OVX or 17\u03b2\u2010oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17\u03b2\u2010oestradiol treatment in\n APOE\u03b53<\/jats:italic>\n mice, but there was no impact of OVX or 17\u03b2\u2010oestradiol in the\n APOE\u03b54<\/jats:italic>\n mice. In cerebral arteries and arterioles, 17\u03b2\u2010oestradiol led to higher mitochondrial complex I respiration in\n APOE\u03b53<\/jats:italic>\n but not\n APOE\u03b54<\/jats:italic>\n mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro\u2010inflammatory factors. Overall these results indicate that the\n APOE<\/jats:italic>\n genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17\u03b2\u2010oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX\n APOE\u03b53<\/jats:italic>\n mice but not in\n APOE\u03b54<\/jats:italic>\n mice. This suggests that 17\u03b2\u2010oestradiol supplementation may have more cerebrovascular benefits for\n APOE\u03b54<\/jats:italic>\n non\u2010carriers.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Females have twice the risk of Alzheimer's disease than males, and the\n APOE\u03b54<\/jats:italic>\n genetic variant has a greater risk for Alzheimer's disease than the\n APOE\u03b53<\/jats:italic>\n variant.\n <\/jats:p>\n <\/jats:list-item>\n \n The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role.<\/jats:p>\n <\/jats:list-item>\n \n \n There are highly inconsistent results among past studies examining the interaction between\n APOE<\/jats:italic>\n genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We aimed to determine the impact of\n APOE\u03b54<\/jats:italic>\n genotype on the cerebrovascular response to ovariectomy and oestradiol.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized\n APOE\u03b53<\/jats:italic>\n mice following ovariectomy.\n <\/jats:p>\n <\/jats:list-item>\n \n \n In contrast\n APOE\u03b54<\/jats:italic>\n mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function.\n <\/jats:p>\n <\/jats:list-item>\n \n \n This research suggests that\n APOE<\/jats:italic>\n genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290852","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T01:32:18Z","timestamp":1781919138000},"page":"5853-5873","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["APOE4<\/i>\n negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-8499","authenticated-orcid":false,"given":"Mackenzie N.","family":"Kehmeier","sequence":"first","affiliation":[{"name":"Department of Human Physiology University of Oregon Eugene Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Famiano","sequence":"additional","affiliation":[{"name":"Department of Human Physiology University of Oregon Eugene Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail 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