Abstract
There is a search for rescue therapy against fetal origins of cardiovascular disease in pregnancy complicated by chronic fetal hypoxia, particularly following clinical diagnosis of fetal growth restriction (FGR). Melatonin protects the placenta in adverse pregnancy; however, whether melatonin protects the fetal heart and vasculature in hypoxic pregnancy independent of effects on the placenta is unknown. Whether melatonin can rescue fetal cardiovascular dysfunction when treatment commences following FGR diagnosis is also unknown. We isolated the effects of melatonin on the developing cardiovascular system of the chick embryo during hypoxic incubation. We tested the hypothesis that melatonin directly protects the fetal cardiovascular system in adverse development and that it can rescue dysfunction following FGR diagnosis. Chick embryos were incubated under normoxia or hypoxia (14% O2) from day 1 ± melatonin treatment (1 mg/kg/day) from day 13 of incubation (term ~21 days). Melatonin in hypoxic chick embryos rescued cardiac systolic dysfunction, impaired cardiac contractility and relaxability, increased cardiac sympathetic dominance, and endothelial dysfunction in peripheral circulations. The mechanisms involved included reduced oxidative stress, enhanced antioxidant capacity and restored vascular endothelial growth factor expression, and NO bioavailability. Melatonin treatment of the chick embryo starting at day 13 of incubation, equivalent to ca. 25 wk of gestation in human pregnancy, rescues early origins of cardiovascular dysfunction during hypoxic development. Melatonin may be a suitable antioxidant candidate for translation to human therapy to protect the fetal cardiovascular system in adverse pregnancy.
Highlights
In addition to the interaction between genetic makeup and traditional lifestyles risk factors, such as smoking, obesity, or a sedentary life, it is established that a component of heart disease-risk can be predetermined by adverse conditions before birth during early development [1, 2]
In hypoxic embryos, plasma melatonin concentrations peaked at similar concentrations (127 Æ 61 pg/mL), this elevation occurred at 2 hr following treatment, after which melatonin decreased more irregularly toward basal levels (Fig. 1)
The data in this study show that treatment of the chronically hypoxic chick embryo with melatonin from day 13 of incubation, equivalent to ca. 25 wk of gestation in human pregnancy, rescues cardiac systolic dysfunction, impaired cardiac contractility and relaxability, increased cardiac sympathetic dominance, and endothelial dysfunction in peripheral circulations
Summary
In addition to the interaction between genetic makeup and traditional lifestyles risk factors, such as smoking, obesity, or a sedentary life, it is established that a component of heart disease-risk can be predetermined by adverse conditions before birth during early development [1, 2]. Our laboratory raised the hypothesis that oxidative stress may be a candidate mechanism linking chronic fetal hypoxia, a fetal origin of cardiovascular dysfunction and programming of cardiovascular disease in the adult offspring [8]. The latter study provided proof of principle to support the hypothesis tested, only high doses of vitamin C incompatible with human treatment were effective to act as an antioxidant in vivo. Both maternal treatment with vitamin C and fetal hypoxia started concurrently in early gestation. There is interest in identifying alternative translational antioxidant therapy in tolerable doses that may rescue cardiovascular dysfunction triggered by chronic fetal hypoxia once diagnosis has been feasible
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