Alterations in uteroplacental hemodynamics during melatonin supplementation in sheep and cattle

Abstract Text:

Compromised placental function can result in fetal growth restriction which is associated with greater risk of neonatal morbidity and mortality. Large increases in transplacental nutrient and waste exchange, which support the exponential increase in fetal growth during the last half of gestation, are dependent primarily on the rapid growth and vascularization of the uteroplacenta. We are examining maternal nutritional plane along with therapeutic supplements, such as dietary melatonin, which impact placental vascularization, blood flow, and fetal development. Using a mid- to late-gestation ovine model of intrauterine growth restriction (n = 31), we examined uteroplacental blood flow and fetal growth during supplementation with 5 mg of dietary melatonin per day. Maternal nutrient restriction decreased uterine artery blood flow, while melatonin supplementation increased umbilical artery blood flow compared to non-supplemented controls. Although melatonin treatment did not rescue fetal weight in nutrient restricted ewes; we did observe disproportionate fetal size and fetal organ development. Moreover, fetal uptake of branched-chain amino acids were partially rescued by dietary melatonin supplementation. Elevated fetal concentrations of melatonin may result in altered blood flow distribution during important time points of development. These specific melatonin responses on umbilical artery hemodynamics and fetal development may be partially mediated through vascular melatonin receptors. Recently, we examined the effects of supplementing Holstein heifers (n = 20) with 20 mg of dietary melatonin per day during the last third of gestation. Uterine artery blood flow was increased by 25% and total serum antioxidant capacity was increased by 43% in melatonin supplemented heifers versus non-supplemented controls. In addition, peripheral concentrations of progesterone were decreased in melatonin supplemented heifers vs. non-supplemented controls. Using an in vitro model, melatonin treatment increased the activity of cytochrome P450 2C, a progesterone inactivating enzyme, which was blocked by treatment with the melatonin receptor antagonist, luzindole. Elucidating the consequences of specific therapeutic supplements on the continual plasticity of placental function will allow us to determine the proper timing and duration for intervention and improvements in offspring growth and development. 

Keywords:

melatonin, umbilical blood flow, uterine blood flow