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Introduction: Recent research indicates an important role in the placental fetal brain axis, with a paucity of information reported in large animals. Melatonin supplementation has been investigated as a potential therapeutic to negate fetal growth restriction. We hypothesized that maternal nutrient restriction and melatonin supplementation would alter neurotransmitter pathways in fetal blood, cotyledonary and hypothalamus tissue., Methods: On day 160 of gestation, Brangus heifers (n = 29 in fall study; n = 25 in summer study) were assigned to one of four treatments: adequately fed (ADQ-CON; 100% NRC recommendation), nutrient restricted (RES-CON; 60% NRC recommendation), and ADQ or RES supplemented with 20 mg/d of melatonin (ADQ-MEL; RES-MEL). Placentomes, fetal blood, and hypothalamic tissue were collected at day 240 of gestation. Neurotransmitters were analyzed in fetal blood and fetal and placental tissues. Transcript abundance of genes in the serotonin pathway and catecholamine pathway were determined in fetal hypothalamus and placental cotyledon., Results: Serotonin was increased (P < 0.05) by 12.5-fold in the blood of fetuses from RES dams versus ADQ in the fall study. Additionally, melatonin supplementation increased (P < 0.05) neurotransmitter metabolites and transcript abundance of the monoamine oxidase A (MAOA) enzyme in the cotyledon. In the summer study, plasma dopamine and placental dopamine receptors were decreased (P < 0.05) in RES dams versus ADQ., Discussion: In conclusion, these data indicate novel evidence of the presence of neurotransmitters and their synthesis and metabolism in the bovine conceptus, which could have greater implications in establishing postnatal behavior., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Prenatal development is reliant on a functioning placenta, which can be influenced by maternal nutrition. Moreover, the variation in cotyledonary capacity within an animal has not been fully examined to date. Therefore, the purpose of this study was to determine the effect of (1) placentome size and (2) maternal nutrient restriction on molecular, microscopic, and macroscopic features of bovine placentomes during late gestation., Methods: Pregnant cows (n = 6) were placed into one of 2 treatments: CON (100% NRC) vs RES (60% of NRC) from day 140 until slaughter at day 240 of gestation. Placentomes of various sizes were perfused to assess macroscopic blood vessel density of the cotyledon. Microscopic imaging and RNA extraction for sequencing was performed., Results: Macroscopic blood vessel density relative to placentome weight was not different (P = 0.42) among small, medium, or large placentomes. Cotyledonary microscopic blood vessel number, area, and perimeter was increased (P < 0.005) in high versus low blood perfusion areas. Differential expressed gene (DEG) analysis showed 209 upregulations and 168 downregulations in the RES group (P ≤ 0.0001). Gene Ontology (GO) analysis showed that downregulated enriched terms were involved in blood vessel and mesenchymal stem cells development, whereas upregulated enriched terms were involved with translation and ribosomal function., Discussion: This study demonstrates that placentome function is uniform across various placentome sizes within an animal. However, microscopic heterogeneity exists within each placentome. Maternal nutrient constraints alter placental transcriptomics which may yield compensatory mechanisms involved in nutrient transport including increased perimeter., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recent research has shown expression of clock genes in peripheral tissue explants, targeting multiple pathways leading to the entrainment of circadian rhythms. Temporal variations are not solely regulated by photoperiod, but factors such as maternal feed availability can entrain fetal circadian clock. Currently, a paucity of information exists for clock gene expression and short-term temporal transcript abundance in the bovine placenta, which is essential for proper offspring development. Therefore, the objective of this study was to determine the effect of early to mid-gestational nutrient restriction on clock genes, angiogenic factors, and nutrient sensing genes mRNA transcript abundance in placental explants during a 24 h period. Placentomes from adequately fed and nutrient restricted heifers were collected via Cesarean section at day 180 of gestation; separated into caruncular and cotyledonary tissue and placed in culture media for a 24 h period. The mRNA transcript abundance of clock genes (ARNTL, CRY1, and PER2), angiogenic factors (HIF1A and VEGFA), and nutrient sensing genes (NAMPT and NR3C1) was determined every 4 h. Clock genes were expressed in caruncular and cotyledonary explant tissue. The caruncular explant transcript abundance of the clock genes was not influenced by time (P > 0.05); while ARNTL abundance decreased over time in the cotyledon explant (P < 0.05). A main effect of time was observed for HIF1A, VEGFA, and NR3C1 in the caruncular tissue (P < 0.05). Although, angiogenic factors and nutrient sensing genes in cotyledonary tissue displayed evident temporal variation in transcript abundance (P < 0.05). Nutrient restriction did not alter (P > 0.15) mRNA transcript abundance of clock genes, angiogenic factors, or nutrient sensing genes in either caruncular or cotyledonary tissue. Interestingly, these data may indicate limited transmission and synchronization of maternal and fetal temporal variations in transcript abundance. These findings demonstrate that multiple timepoint collections are needed in future studies due to the innate existence of temporal oscillations observed in the bovine placenta., Competing Interests: Declaration of competing interest The authors declare that there is not an existent conflict of interest in this research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

As the demand for food increases with exponential growth in the world population, it is imperative that we understand how to make livestock production as efficient as possible in the face of decreasing available natural resources. Moreover, it is important that livestock are able to meet their metabolic demands and supply adequate nutrition to developing offspring both during pregnancy and lactation. Specific nutrient supplementation programs that are designed to offset deficiencies, enhance efficiency, and improve nutrient supply during pregnancy can alter tissue vascular responses, fetal growth, and postnatal offspring outcomes. This review outlines how vascularity in nutrient transferring tissues, namely the maternal gastrointestinal tract, the utero-placental tissue, and the mammary gland, respond to differing nutritional planes and other specific nutrient supplementation regimes.

Previously we reported increased umbilical artery blood flow in ewes supplemented with melatonin from mid- to late-pregnancy, while maternal nutrient restriction decreased uterine artery blood flow. To further unravel these responses, this study was designed to assess placental cell proliferation and vascularity following supplementation with melatonin or maternal nutrient restriction. For the first experiment, 31 primiparous ewes were supplemented with 5mg of melatonin per day (MEL) or no melatonin (CON) and allocated to receive 100% (adequate fed; ADQ) or 60% (restricted; RES) of their nutrient requirements from day 50 to 130 of gestation. To examine melatonin receptor dependent effects, a second experiment was designed utilizing 14 primiparous ewes infused with vehicle, melatonin, or luzindole (melatonin receptor 1 and 2 antagonist) from day 62 to 90 of gestation. For experiment 1, caruncle concentrations of RNA were increased in MEL-RES compared to CON-RES. Caruncle capillary area density and average capillary cross-sectional area were decreased in MEL-RES compared to CON-RES. Cotyledon vascularity was not different across dietary treatments. For experiment 2, placental cellular proliferation and vascularity were not affected by infusion treatment. In summary, melatonin interacted with nutrient restriction to alter caruncle vascularity and RNA concentrations during late pregnancy. Although melatonin receptor antagonism alters feto-placental blood flow, these receptor dependent responses were not observed in placental vascularity. Moreover, placental vascularity measures do not fully explain the alterations in uteroplacental blood flow., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This review discusses the importance of placental vascular development, as reflected by placental angiogenesis and placental blood flow, to placental function in normal pregnancies. We then summarize our current understanding of how maternal stress, including inadequate maternal nutrition as well as the application of assisted reproductive technologies (ART), leads to compromised placental angiogenesis and function and the subsequent effects on fetal and neonatal growth and development. Finally, we discuss several promising therapeutic approaches to 'rescue' placental vascular development and function in compromised pregnancies, leading to improved pregnancy and postnatal outcomes.

Dietary melatonin supplementation from mid- to late gestation increases umbilical artery blood flow and causes disproportionate fetal growth. Melatonin receptors have been described throughout the cardiovascular system; however, there is a paucity of data on the function of placental melatonin receptors. The objectives of the current experiment were to determine fetal descending aorta blood flow, umbilical artery blood flow, and placental and fetal development following a 4-wk uterine infusion of melatonin (MEL), melatonin receptor 1 and 2 antagonist (luzindole; LUZ), or vehicle (CON) from Day 62 to Day 90 of gestation. After 4 wk of infusion, umbilical artery blood flow and umbilical artery blood flow relative to placentome weight were increased (P < 0.05) in MEL- versus CON- and LUZ-infused dams. Fetal descending aorta blood flow was increased (P < 0.05) in MEL- versus CON- and LUZ-infused dams, while fetal descending aorta blood flow relative to fetal weight was increased in MEL- versus CON-infused dams and decreased in LUZ- versus CON-infused dams. Following the 4-wk infusion, we observed an increase in placental efficiency (fetal-placentome weight ratio) in MEL- versus LUZ-infused dams. The increase in umbilical artery blood flow due to chronic uterine melatonin infusion is potentiated by an increased fetal cardiac output through the descending aorta. Moreover, melatonin receptor antagonism decreased fetal descending aorta blood flow relative to fetal weight. Therefore, melatonin receptor activation may partially mediate the observed increase in fetal blood flow following dietary melatonin supplementation.

As placental growth and vascularity precedes exponential fetal growth, not only is proper establishment of the placenta important, but also a continual plasticity of placental function throughout gestation. Inadequate maternal environment, such as nutritional plane, has been documented to alter fetal organogenesis and growth, thus leading to improper postnatal growth and performance in many livestock species. The timing and duration of maternal nutritional restriction appears to influence the capillary vascularity, angiogenic profile and vascular function of the placenta in cattle and sheep. In environments where fetal growth and/or fetal organogenesis are compromised, potential therapeutics may augment placental nutrient transport capacity and improve offspring performance. Supplementation of specific nutrients, including protein, as well as hormone supplements, such as indolamines, during times of nutrient restriction may assist placental function. Current use of Doppler ultrasonography has allowed for repeated measurements of uterine and umbilical blood flow including assessment of uteroplacental hemodynamics in cattle, sheep and swine. Moreover, these variables can be monitored in conjugation with placental capacity and fetal growth at specific time points of gestation. Elucidating the consequences of inadequate maternal intake on the continual plasticity of placental function will allow us to determine the proper timing and duration for intervention.

The objective of the current study was to examine the effects of supplemental melatonin implants on uterine artery blood flow from mid to late gestation in beef cattle and subsequent development of their male offspring. Commercial beef heifers (n = 32) and cows (n = 25) were bred via artificial insemination and assigned to 1 of 2 groups supplemented with melatonin implants (MEL) or without (CON) at day 180, 210, and 240 of gestation. Uterine artery blood flow was determined using color Doppler ultrasonography. A subset of 12 crossbred heifers (n = 6 MEL; n = 6 CON) underwent Cesarean sections on day 243 ± 2 of gestation to allow for placentome collection. Maternal and fetal serum were collected to analyze melatonin concentrations. The remaining cattle were allowed to calve and at weaning (195 ± 2 d of age), bull calves (n = 15) were castrated and testicular tissue harvested for seminiferous tubule analysis. Heifer uterine artery blood flow was increased (P = 0.009) at day 240 of gestation in MEL compared with CON heifers. Cow uterine artery blood flow was increased (P = 0.003) in MEL compared with CON cows irrespective of gestational day. Maternal and fetal concentrations of melatonin were increased (P < 0.05) in MEL compared with CON heifers. The percent of placentome capillary area per mm2 was decreased (P = 0.019) in MEL compared with CON heifers, while cotyledonary ANGPT1 mRNA tended to increase (P = 0.095) in MEL compared with CON heifers. At weaning, body weight of male offspring and their scrotal circumference were increased (P < 0.05) in calves born to MEL compared with CON dams, while seminiferous tubule diameter and area were not different (P > 0.40) between treatments. In summary, melatonin supplementation increased uterine artery blood flow in mid to late gestating cattle, but this was not accompanied by an increase in fetal weight. Alterations in postnatal development of bulls, including increased body weight and scrotal circumference, warrants future investigations related to attainment of puberty and subsequent fertility of offspring born to melatonin supplemented dams. [ABSTRACT FROM AUTHOR]

The placenta modulates fetal brain development in mice and humans, with a paucity of information reported in cattle. The objective was to determine the effects of maternal nutrient restriction and melatonin supplementation on neurotransmitter concentrations in the cotyledon, fetal hypothalamus, and fetal blood. At day 160 of gestation, 29 spring-calving and 25 fall-calving Brangus heifers were assigned treatments: adequately fed (ADQ-CON; 100% NRC recommendation), nutrient restricted (RES-CON; 60% NRC recommendation), and ADQ or RES supplemented with 20 mg/d of melatonin (ADQ-MEL; RESMEL). Fetuses were removed at day 240 of gestation for collection of placentomes, blood, and hypothalamic tissue. Neurotransmitters (serotonin, 5-HT; dopamine, DA; norepinephrine, NE; epinephrine, EPI) and metabolites (3,4-dihydroxyphenylacetic acid, DOPAC; 5-hydroxyindoleacetic acid, 5-HIAA; homovanillic acid HVA) were analyzed by LCMS or HPLC in blood or tissues, respectively. Data were analyzed by ANOVA using the mixed procedure in SAS with seasons analyzed separately. In spring-calving heifers, melatonin increased (P = 0.05) concentrations of DOPAC, DA, 5-HIAA, and HVA in the cotyledon. Nutrient restriction and melatonin supplementation increased (P = 0.05) blood 5-HT. In both calving seasons, there was a nutrition by treatment interaction in hypothalamic 5-HT (P = 0.01), whereby RES-MEL was increased compared with ADQ-MEL. For fall-calving heifers, no differences were observed in neurotransmitter concentrations in the cotyledon. Hypothalamic NE was increased (P = 0.02) in RES vs. ADQ, while hypothalamic and blood DA were decreased (P = 0.05) in RES vs. ADQ. Hypothalamic 5-HIAA was increased (P = 0.05) in the MEL vs. CON, while blood EPI was decreased (P = 0.04) in MEL vs. CON. In summary, nutrient restriction and melatonin supplementation alter concentrations of neurotransmitters and their metabolites in a seasonally dependent manner. Further investigation into the gene expression of these neurotransmitter pathways is necessary to better define the bovine placental-brain axis. [ABSTRACT FROM AUTHOR]

As placental growth and vascularity precedes exponential fetal growth, not only is proper establishment of the placenta important, but also a continual plasticity of placental function throughout gestation. Inadequate maternal environment, such as nutritional plane, has been documented to alter fetal organogenesis and growth, thus leading to improper postnatal growth and performance in many livestock species. The timing and duration of maternal nutritional restriction appears to influence the capillary vascularity, angiogenic profile and vascular function of the placenta in cattle and sheep. In environments where fetal growth and/or fetal organogenesis are compromised, potential therapeutics may augment placental nutrient transport capacity and improve offspring performance. Supplementation of specific nutrients, including protein, as well as hormone supplements, such as indolamines, during times of nutrient restriction may assist placental function. Current use of Doppler ultrasonography has allowed for repeated measurements of uterine and umbilical blood flow including assessment of uteroplacental hemodynamics in cattle, sheep and swine. Moreover, these variables can be monitored in conjugation with placental capacity and fetal growth at specific time points of gestation. Elucidating the consequences of inadequate maternal intake on the continual plasticity of placental function will allow us to determine the proper timing and duration for intervention. [ABSTRACT FROM AUTHOR]

Placental and fetal development is especially sensitive to direct and indirect effects of the maternal environment. The duration and timing of environmental insults or stimuli in relation to the stage of gestation influences the phenotypic outcomes of offspring. Nutrient restriction during early gestation, such as developing heifers on low-input forage-based management schemes followed by nutrient re-alimentation at pregnancy confirmation, increased late-term uterine artery blood flow relative to maternal body weight compared with conventionally developed heifers. In this study, calf birth weights were not different between low-input vs conventionally developed heifers, which may indicate a compensatory mechanism to safeguard late-term fetal growth. In comparison, nutrient restriction during early to mid-gestation (from day 50 to 180 of pregnancy) decreased uterine artery blood flow, decreased fetal weight, and increased placental blood vessel density in both Brahman and Angus heifers. Moreover, the efficiency of uterine artery blood flow relative to fetal weight was improved in nutrient restricted dams versus adequate fed as well as Brahman vs Angus. These responses indicate improved placental nutrient supply following early to mid-gestation nutrient restriction. Apart from nutritional management, season and melatonin supplementation impacts placental nutrient supply in cattle. Specifically, spring calving heifers with increased uterine artery blood flow had heavier calves at birth compared with their fall calving counterparts. Although several seasonal environmental changes can influence performance and reproductive traits, specific changes in hormone concentrations as a result of photoperiod may alter blood distribution to the reproductive tract. This is apparent when supplementing dairy heifers and beef cows with melatonin during the last third of pregnancy, which increased uterine artery blood flow and calf weaning weights compared with non-supplemented controls. Elucidating the consequences of specific supplements on the continual plasticity of placental nutrient supply will allow us to determine important mediators of fetal growth and development. [ABSTRACT FROM AUTHOR]