Seasonal and Temporal Variation in the Placenta during Melatonin Supplementation in a Bovine Compromised Pregnancy Model

Compromised pregnancies result in poorly functioning placenta restricting the amount of oxygen and nutrient supply to the fetus resulting in intrauterine growth restriction (IUGR). Supplementing dietary melatonin during a compromised pregnancy increased uteroplacental blood flow and prevented IUGR in a seasonal dependent manner. The objectives were to evaluate seasonal melatonin-mediated changes in temporal alterations of the bovine placental vascularity and transcript abundance of clock genes, angiogenic factors, and nutrient sensing genes in 54 underfed pregnant Brangus heifers (Fall, n = 29; Summer, n = 25). At d160 of gestation, heifers were assigned to treatments consisting of adequately fed (ADQ-CON; 100% NRC; n = 13), nutrient restricted (RES-CON; 60% NRC; n = 13), and ADQ or RES supplemented with 20 mg/d of melatonin (ADQ-MEL, n = 13; RES-MEL, n = 15). The animals were fed daily at 0900 h until d 240 where Cesarean sections were performed in the morning (0500 h) or afternoon (1300 h) for placentome collections. In both seasons, we observed a temporal alteration of the core clock genes in the cotyledonary tissue in a season dependent manner. In the fall, ARNTL, CLOCK, NR1D1, and RORA transcript abundance were decreased (P ≤ 0.05) in the afternoon compared to the morning; whereas in the summer, ARNTL, PER2, and RORA expression were increased (P ≤ 0.05) in the afternoon. Interestingly, in both seasons, there was a concomitant temporal increase (P ≤ 0.05) of cotyledonary blood vessel perfusion and caruncular melatonin receptor 1A transcript abundance. Melatonin supplementation did not alter the melatonin receptor 1A transcript abundance (P > 0.05), however, in the summer, melatonin supplementation increased cotyledonary VEGFA, CRY1, and RORA (P ≤ 0.05) transcript abundance. In addition, during the summer the placentomes from underfed dams had increased average capillary size and HIF1α transcript abundance compared to adequately fed (P ≤ 0.05). In conclusion, these data indicate increased cotyledonary blood vessel size and blood distribution after feeding to better facilitate nutrient transport. Interestingly, maternal nutritional plane appears to play a crucial role in regulating the bovine placental circadian clock. Based on these findings, the regulation of angiogenic factors and clock genes in the bovine placenta appear to be an underlying mechanism of the therapeutic effect of dietary melatonin supplementation in the summer.