{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T23:50:05Z","timestamp":1784073005702,"version":"3.55.0"},"reference-count":42,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Metformin is increasingly used to treat diabetes in pregnancy, but the effects on adult offspring health remain under\u2010explored. The present study investigated the long\u2010term cardiovascular effects in male and female offspring of maternal metformin treatment using a well\u2010established mouse model of obese glucose intolerant pregnancy. Female mice were given chow, or an obesogenic diet with\/without 300\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0day<jats:sup>\u22121<\/jats:sup> oral metformin during gestation. At 3, 6 and 12\u00a0months of age, male and female offspring were studied longitudinally with tail\u2010cuff plethysmography and echocardiography. At 12\u00a0months, tissues were collected for wire myography, histology and molecular analyses. Female offspring of obese dams had elevated blood pressure throughout life, cardiac diastolic dysfunction at 3\u00a0months, and increased femoral vasoconstrictor reactivity and aortic wall remodelling at 12\u00a0months. Metformin treatment did not ameliorate these effects and led to obesity\u2010induced hypertension at 12\u00a0months. Irrespective of metformin, male offspring of obese pregnancy had cardiac diastolic dysfunction from 6\u00a0months without changes in blood pressure. Male metformin\u2010exposed offspring also showed cardiomegaly, increased cardiac collagen and vascular sympathetic hyperreactivity, suggesting metformin exposure worsened the cardiovascular phenotype. These findings show that maternal obesity caused sex\u2010specific cardiovascular aberrations in aged offspring. Maternal metformin was not corrective and introduced further sex\u2010dependent cardiovascular alterations. Further long\u2010term offspring follow up of both sexes is needed for informed decisions about metformin during pregnancy.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16812-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The oral medication metformin is increasingly used to treat diabetes in pregnancy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin readily crosses the placenta, and long\u2010term effects on offspring cardiovascular health remain unexplored in human and animal studies.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In a mouse model of maternal diet\u2010induced obesity with impaired glucose tolerance, female and male offspring developed hypertension and diastolic cardiac dysfunction, respectively, by 12\u00a0months of age (equivalent to middle age in humans).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Maternal metformin treatment worsened the cardiovascular phenotype and introduced further sex\u2010dependent cardiovascular alterations in both male (cardiac stiffening, vascular dysfunction) and female (obesity\u2010induced hypertension) offspring.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This work highlights that long\u2010term cardiovascular follow up in offspring of both sexes from human pregnancies treated with metformin is crucial to make more informed decisions about metformin use in diabetic pregnancy.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp288696","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T02:18:56Z","timestamp":1750385936000},"page":"4747-4764","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cardiovascular outcome in 12\u2010month\u2010old male and female offspring of metformin\u2010treated obese mice"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2893-7199","authenticated-orcid":false,"given":"Josca M.","family":"Schoonejans","sequence":"first","affiliation":[{"name":"Institute of Metabolic Science\u2010Metabolic Research Laboratories and MRC Metabolic Diseases Unit University of Cambridge  Cambridge UK"},{"name":"Institute of Reproductive Biology, Department of Metabolism, Digestion and Reproduction Imperial College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-5043","authenticated-orcid":false,"given":"Phoebe","family":"Wilsmore","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science\u2010Metabolic Research Laboratories and MRC Metabolic Diseases Unit University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9326-7649","authenticated-orcid":false,"given":"Lais V.","family":"Mennitti","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science\u2010Metabolic Research Laboratories and MRC Metabolic Diseases Unit University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6378-3434","authenticated-orcid":false,"given":"Kwun K.","family":"Wong","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science\u2010Metabolic Research Laboratories and MRC Metabolic Diseases Unit University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Ashmore","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science\u2010Metabolic Research Laboratories and MRC Metabolic Diseases Unit University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-7939","authenticated-orcid":false,"given":"Tessa A. 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