Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy

Abstract

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2) pregnancy ± melatonin (M) treatment (5 μg·ml−1.day−1) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15–20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia‐induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair‐fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in‐vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair‐fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch‐up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia‐induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair‐fed pregnancies. Whilst maternal treatment of normoxic or pair‐fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

“…8 Offspring of hypoxic pregnancies display cardiac abnormalities in adulthood and appear to be sensitized to ischemia/reperfusion injury. 7,[9][10][11][12][13][14][15][16][17] These findings support epidemiological evidence from human pregnancies, which show hypoxia during development can increase the risk of cardiac dysfunction in offspring. [18][19][20][21][22][23] Combined, evidence derived from human clinical studies and from experimental preclinical models strongly supports that fetal hypoxia is an independent risk factor for offspring cardiovascular disease.…”

“…Several studies have shown that antioxidants can prevent fetal cardiac remodeling and dysfunction in adulthood, such as maternal treatment with vitamin C, allopurinol, statins, MitoQ, and melatonin. 9,11,[36][37][38][39][40][41] Antioxidant protection on the offspring of hypoxic pregnancy manifests in several ways, including enhanced antioxidant capacity, improvements in transplacental oxygenation, diminished endothelial dysfunction, and normalization of arterial blood pressure. 38 Interestingly, the protective effects are enhanced if mitochondria-targeted antioxidants, such as MitoQ, are used, 39 suggesting ROS production from the mitochondria may play a significant role in programming cardiac dysfunction.…”

“…45,47,48 Importantly, recent studies have shown that treatment of hypoxic pregnancies with melatonin prevented all alterations in cardiovascular structure and function in adult offspring. 11 Melatonin is already being used in clinical trials for complicated pregnancies, [49][50][51] and can readily cross the placenta. 11 However, nothing is known about the effects of melatonin on fetal cardiac mitochondrial function.…”

“…11 Melatonin is already being used in clinical trials for complicated pregnancies, [49][50][51] and can readily cross the placenta. 11 However, nothing is known about the effects of melatonin on fetal cardiac mitochondrial function.…”

Exogenous Melatonin Directly and Indirectly Influences Sheep Oocytes

“…Implanting MT affects all body organs and produces side effects such as promoting the growth of goat hair ( 74 ). It also affects the cardiovascular system ( 75 ), the neurological system ( 76 ), the endocrine system ( 77 ), and metabolism ( 78 ). Thus, implanting MT in non-breeding seasons should consider the effects on animal welfare.…”