{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:15:34Z","timestamp":1789416934740,"version":"build-2803163510"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"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":[[2026,1]]},"abstract":"\n Abstract<\/jats:title>\n \n Fetal growth restriction (FGR) increases the risk of cardiovascular disease. FGR is linked to placental insufficiency and fetal hypoxemia, leading to oxidative stress and inflammation, which collectively influence the developmental programming of cardiovascular disease. This study assessed whether melatonin (MLT), a potent antioxidant and anti\u2010inflammatory agent, could prevent cardiovascular deficits associated with FGR. Placental insufficiency was induced in ewes at 89\u00a0days of gestational age (dGA, term 148\u00a0dGA). Ewes were randomly allocated to control, FGR or FGR+MLT (\n i.v.<\/jats:sc>\n , 15\u00a0mg\u00a0day\n \u22121<\/jats:sup>\n , from 95\u00a0dGA to birth) groups. Lambs were delivered preterm at 136\u00a0dGA and assessed as newborn (24\u00a0h) and 4\u2010week\u2010old lambs. Vascular function was determined in femoral arteries using\n in vitro<\/jats:italic>\n wire myography and vascular morphology as assessed in carotid and femoral arteries. Newborn FGR lambs were \u223c30% smaller than control lambs with an increased brain\u2010to\u2010body weight ratio, indicative of brain sparing. Femoral endothelial function declined between \u223c24\u00a0h after birth and 4\u00a0weeks in FGR lambs. By contrast, femoral arteries from newborn FGR+MLT lambs displayed transient endothelial dysfunction that improved by 4\u00a0weeks. However, these arteries showed elevated levels of oxidative stress and inflammation. Despite improving endothelial function, melatonin also disrupted the brain\u2010sparing response in FGR lambs. Furthermore, by 4\u00a0weeks of age, melatonin treatment led to heightened oxidative stress and inflammatory markers in the peripheral vasculature, suggesting a potential trade\u2010off between vascular benefits and systemic maladaptation. These findings highlight the complexity of melatonin's effects on the cardiovascular system and underscore the need for careful evaluation of its long\u2010term safety and efficacy before clinical translation.\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 Fetal growth restriction (FGR) significantly increases the lifelong risk of cardiovascular disease, and there are currently no targeted treatments to mitigate these risks.<\/jats:p>\n <\/jats:list-item>\n \n This study follows growth\u2010restricted lambs from birth to 4\u00a0weeks of age (comparable to a 1\u2010year\u2010old human in terms of cardiovascular function) to characterise how FGR affects vascular development over time.<\/jats:p>\n <\/jats:list-item>\n \n FGR lambs exhibited progressive endothelial dysfunction in the femoral artery, but antenatal melatonin treatment restored endothelial function long\u2010term despite the presence of vascular oxidative stress and inflammation.<\/jats:p>\n <\/jats:list-item>\n \n The brain\u2010sparing response is a key adaptive mechanism for fetal survival, yet melatonin appears to dampen this response, highlighting the need for further investigation into its broader physiological effects.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp288750","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T15:24:36Z","timestamp":1763047476000},"page":"193-213","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Antenatal melatonin for cardiovascular deficits in fetal growth restriction"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-4175","authenticated-orcid":false,"given":"Charmaine R.","family":"Rock","sequence":"first","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical 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