Antenatal melatonin for cardiovascular deficits in fetal growth restriction

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-inflammatory agent, could prevent cardiovascular deficits associated with FGR. Placental insufficiency was induced in ewes at 89 days of gestational age (dGA, term 148 dGA). Ewes were randomly allocated to control, FGR or FGR+MLT (i.v., 15 mg day^-1, from 95 dGA to birth) groups. Lambs were delivered preterm at 136 dGA and assessed as newborn (24 h) and 4-week-old lambs. Vascular function was determined in femoral arteries using in vitro wire myography and vascular morphology as assessed in carotid and femoral arteries. Newborn FGR lambs were ∼30% smaller than control lambs with an increased brain-to-body weight ratio, indicative of brain sparing. Femoral endothelial function declined between ∼24 h after birth and 4 weeks in FGR lambs. By contrast, femoral arteries from newborn FGR+MLT lambs displayed transient endothelial dysfunction that improved by 4 weeks. However, these arteries showed elevated levels of oxidative stress and inflammation. Despite improving endothelial function, melatonin also disrupted the brain-sparing response in FGR lambs. Furthermore, by 4 weeks of age, melatonin treatment led to heightened oxidative stress and inflammatory markers in the peripheral vasculature, suggesting a potential trade-off 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-term safety and efficacy before clinical translation. KEY POINTS: Fetal growth restriction (FGR) significantly increases the lifelong risk of cardiovascular disease, and there are currently no targeted treatments to mitigate these risks. This study follows growth-restricted lambs from birth to 4 weeks of age (comparable to a 1-year-old human in terms of cardiovascular function) to characterise how FGR affects vascular development over time. FGR lambs exhibited progressive endothelial dysfunction in the femoral artery, but antenatal melatonin treatment restored endothelial function long-term despite the presence of vascular oxidative stress and inflammation. The brain-sparing 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.