IL-33 supplementation improves uterine artery resistance and maternal hypertension in response to placental ischemia.

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized that IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 µg/kg/day) into normal pregnant (NP) and RUPP rats from gestation day 14 to 19. We found that IL-33 supplementation in RUPP rats reduces maternal blood pressure and improves the uterine artery resistance index (UARI). In addition to physiological improvements, we found decreased circulating and placental cytolytic Natural Killer cells (cNKs) and decreased circulating, placental, and renal TH17s in IL-33-treated RUPP rats. cNK cell cytotoxic activity also decreased in IL-33-supplemented RUPP rats. Furthermore, renal ROS and placental preproendothelin-1 (PPET-1) decreased in RUPP rats treated with IL-33. These findings demonstrate a role for IL-33 in controlling vascular function and maternal BP during pregnancy by decreasing inflammation, renal ROS, and PPET-1 expression. These data suggest that IL-33 may have therapeutic potential in managing PE.NEW & NOTEWORTHY Though decreased IL-33 signaling has been clinically associated with PE, the mechanisms linking this signaling pathway to overall disease pathophysiology are not well understood. This study provides compelling evidence that mechanistically links reduced IL-33 with the inflammatory response and vascular dysfunction observed in response to placental ischemia, such as in PE. Data presented in this study submit the IL-33 signaling pathway as a possible therapeutic target for the treatment of PE.

Preliminary Study of Iron Concentration in the Human Placenta in Twin Pregnancies.

BACKGROUND: Pregnancy significantly increases the demand for iron (Fe) in the female body to facilitate maternal blood volume expansion, placental development, and fetal growth. As Fe flux in pregnancy is significantly influenced by the placenta, the aim of this study was to determine the dependencies between the Fe concentration in the placenta, the infant's morphometric parameters and the woman's morphological blood parameters in the last trimester. METHODS: The study was conducted on 33 women with multiple (dichorionic-diamniotic) pregnancies from whom the placentas were drawn, and their 66 infants, including pairs of monozygotic (n = 23) and mixed-sex twins (n = 10). Fe concentrations were determined based on inductively coupled plasma atomic emission spectroscopy (ICP-OES) using ICAP 7400 Duo, Thermo Scientific. RESULTS: The results of the analysis showed that lower placental Fe concentrations were associated with deteriorated morphometric parameters of infants, including weight and head circumference. Although we found no statistically significant dependencies between Fe concentration in the placenta and the women's morphological blood parameters, higher Fe concentration in the placenta of mothers supplemented with Fe correlated with better morphometric parameters in infants compared to those whose mothers received no Fe supplementation. CONCLUSIONS: The research adds additional knowledge for placental iron-related processes during multiple pregnancies. However, many limitations of the study do not allow detailed conclusions to be assessed, and statistical data should be assessed conservatively.

Dietary supplements and vascular function in hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy are complications that can lead to maternal and infant mortality and morbidity. Hypertensive disorders of pregnancy are generally defined as hypertension and may be accompanied by other end organ damages including proteinuria, maternal organ disturbances including renal insufficiency, neurological complications, thrombocytopenia, impaired liver function, or uteroplacental dysfunction such as fetal growth restriction and stillbirth. Although the causes of these hypertensive disorders of pregnancy are multifactorial and elusive, they seem to share some common vascular-related mechanisms, including diseased spiral arteries, placental ischemia, and endothelial dysfunction. Recently, preeclampsia is being considered as a vascular disorder. Unfortunately, due to the complex etiology of preeclampsia and safety concerns on drug usage during pregnancy, there is still no effective pharmacological treatments available for preeclampsia yet. An emerging area of interest in this research field is the potential beneficial effects of dietary intervention on reducing the risk of preeclampsia. Recent studies have been focused on the association between deficiencies or excesses of some nutrients and complications during pregnancy, fetal growth and development, and later risk of cardiovascular and metabolic diseases in the offspring. In this review, we discuss the involvement of placental vascular dysfunction in preeclampsia. We summarize the current understanding of the association between abnormal placentation and preeclampsia in a vascular perspective. Finally, we evaluate several studied dietary supplementations to prevent and reduce the risk of preeclampsia, targeting placental vascular development and function, leading to improved pregnancy and postnatal outcomes.

Seasonal and temporal variation in the placenta during melatonin supplementation in a bovine compromised pregnancy model.

Compromised pregnancies result in a 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 day 160 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 hours until day 240 where Cesarean sections were performed in the morning (0500 hours) or afternoon (1300 hours) 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 those 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, the 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 appears to be an underlying mechanism of the therapeutic effect of dietary melatonin supplementation in the summer.

Maternal nutrient restriction during the last trimester of pregnancy impairs the fetal development, increases morbidity and mortality, and reduces its performance in adult life. Animals with compromised pregnancies exhibit a reduction in uterine blood flow thereby limiting the nutrients available for the fetus to grow and develop. Melatonin, a hormone that many people use as a sleep aid, could be a solution as a potential therapeutic in cattle since it has antioxidant properties and has been shown to regulate blood flow and rescue fetal weight during compromised pregnancies. In the current study, we examined the changes in placental vascularity and gene expression when supplementing underfed dams with dietary melatonin during late gestation in a group of fall-calving and spring-calving heifers. Contrary to our hypothesis melatonin did not control the placental circadian clock gene network, while maternal nutrient restriction disrupted the gene expression in the placenta. Furthermore, this study found that gene expression in the placenta is seasonally dependent.

Maternal folate status and placental vascular malperfusion: Findings from a high-risk US minority birth cohort.

INTRODUCTION: Maternal folate deficiency was associated with preeclampsia (PE) and PE was associated with placental maternal vascular malperfusion (MVM). However, no study has examined the association of maternal folate status with placental MVM. METHODS: We examined the association of maternal folate status and placental MVM in the Boston Birth Cohort. Primary exposure variables were maternal self-reported multivitamin supplement (<2, 3-5, >5 times/week) per trimester; and plasma folate levels (nmol/L) after birth. Primary outcome was presence/absence of placental MVM defined by the Amsterdam Placental Workshop Group standard classification. Covariates included demographics, chronic hypertension, clinically diagnosed PE, eclampsia and HELLP syndrome, gestational and pre-gestational diabetes, overweight/obesity, maternal cigarette smoking and alcohol use. Associations between folate and placental MVM were evaluated using multivariate logistic regressions. RESULTS: Of 3001 mothers in this study, 18.8% of mothers had PE, 37.5% had MVM. Mothers with the lowest self-reported frequency of folate intake had the highest risk of MVM (OR 1.45, 95% CI 1.03-2.05), after adjusting for the covariates. Consistently, among a subset of 939 mothers with plasma folate levels, folate insufficiency was associated with increased risk of MVM (OR 1.65, 95% CI 1.03-2.63), after adjusting for the covariables. As expected, mothers with low folate and placental MVM had highest rates of PE compared to those of high folate and no MVM (p < 0.001). DISCUSSION: In this high-risk birth cohort, low maternal folate status was associated with increased risk of placental MVM. Further investigation should explore the association between folate status, placental findings and the great obstetrical syndrome.

Maternal magnolol supplementation alters placental morphology, promotes placental angiogenesis during mid-gestation and improves offspring growth in a pregnant mouse model.

The placenta is the organ that determines the growth of the fetus and the outcome of pregnancy. Magnolol is a multifunctional polyphenol with antioxidant, anti-inflammatory, anticancer and neuroprotective functions. However, there is less knowledge of the effects or complications in the placenta and the mechanism underlying the effect of magnolol when used during pregnancy. The aim of this study was to explore the effects of maternal magnolol supplementation on pregnancy outcomes and placental alterations in a pregnant mouse model. A total of 128 pregnant mice were randomly divided into 4 groups supplemented with 0, 40, 80 and 160 µM magnolol from gestational day 0 (GD0) to delivery. Our results revealed that the number of large-for-gestation-age fetuses on GD13 and the weaning weight of offspring were increased in the magnolol treatment groups. Moreover, maternal magnolol supplementation increased superoxide dismutase (SOD), decreased malondialdehyde (MDA) in maternal serum, and promoted the expression of heme oxygenase-1 (HO-1) in the placenta. Furthermore, magnolol significantly increased the area of the junctional zone and decidua in the placentas and increased the expression of interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), chemokine (CC Motif) Ligand 3 (CCL3), chemokine (CXC motif) ligand 10 (CXCL10), insulin-like growth factor-1 (IGF-1) and T-box transcription factor 21 (T-bet) in the placenta during GD13 in pregnant mice, while suppressor of cytokine signaling 1 (SOCS1) was reduced. Moreover, the ratio of blood space in the labyrinth area, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were all increased in the magnolol treatment groups on GD13. Taken together, these results indicate that magnolol can improve the growth of offspring, which might be due to the alteration of placental morphology and the promotion of placental angiogenesis during mid-gestation.

Effects of Umbilical Cord Milking on Term Infants Delivered by Cesarean Section.

OBJECTIVE: Umbilical cord milking (UCM) is an efficient way to achieve optimal placental transfusion in term infants born by cesarean section (CS). However, it is not frequently performed due to concern for short-term adverse effects of increased blood volume, such as polycythemia and hyperbilirubinemia. The aim of this study is to evaluate the short-term effects of UCM on term infants delivered by CS. STUDY DESIGN: We conducted a pre- and postimplementation cohort study comparing term infants delivered by CS who received UCM five times (141 infants, UCM group) during a 6-month period (August 1, 2017 to January 31, 2018) to those who received immediate cord clamping (ICC) during the same time period (105 infants, postimplementation ICC) and during a 3-month period (October1, 2016 to December 31, 2016) prior to the implementation of UCM (141 infants, preimplementation ICC). RESULTS: Mothers were older in UCM group compared with both ICC groups. There were no significant differences in other maternal or neonatal characteristics. Although this study was not powered to detect differences in outcomes, the occurrence of hyperbilirubinemia needing phototherapy, symptomatic polycythemia, NICU admissions, or readmissions for phototherapy was similar between the groups. CONCLUSION: UCM intervention was not associated with increased incidence of phototherapy or symptomatic polycythemia in term infants delivered by CS.

The risk of hyperbilirubinemia in term neonates after placental transfusion - a randomized-blinded controlled trial.

OBJECTIVE: We aimed to demonstrate non-inferiority of delayed cord clamping (DCC) and cord milking (CM) in comparison to early cord clamping (ECC) in the incidence of hyperbilirubinemia requiring phototherapy. MATERIAL AND METHODS: 467 of maternal-foetal dyads were screened for eligibility. 389 term infants, of breastfeeding, non-smoking mothers were randomized to receive ECC ( < 40 s), DCC (1-2 min) or CM (4 times towards the neonate). The primary outcome was defined as hyperbilirubinemia requiring phototherapy. RESULTS: 307 patients were included in the analysis. CM did not increase the risk of phototherapy RR 11.27 95% CI (0.80; 2.04). Similar results were achieved when comparing DCC and ECC, RR 1.29 95% CI (0.82; 2.05). This was also true for CM vs DCC, RR 0.99 95% CI (0.64; 1.52). The prevalence of total serum bilirubin (TSB) at 24-48 hours was 10.8 mg/dL; 10.33 mg/dL and 11.39 in ECC, CM and DCC group respectively. Transcutaneous bilirubin (TcB) levels at 24-48 h were 7.58 mg/dL, 7.89 mg/dL and 7.60 mg/dL in the ECC, CM and DCC respectively. None of the neonates met exchange transfusion criteria or symptomatic polycythaemia. CONCLUSIONS: Our study suggests that placental transfusion is not associated with hyperbilirubinemia requiring phototherapy or exchange transfusion.

Transfer and Vascular Effect of Endothelin Receptor Antagonists in the Human Placenta.

Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ETAR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETAR/ETBR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ETBR antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ETAR, and ETBR were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ETAR exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.

Addition of sildenafil citrate for treatment of severe intrauterine growth restriction: a double blind randomized placebo controlled trial.

Background: Severe intrauterine growth restriction complicates approximately 0.4% of the pregnancies. It increases the risk of perinatal morbidity and mortality.Subjects and methods: A double blind placebo controlled trial was conducted in Beni Suef University hospitals during 2017. It included 46 pregnant women with severe intrauterine growth restriction. Women were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20 mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Primary outcomes included improvement in umbilical and middle cerebral arteries pulsatility indices and abdominal circumference.Results: Umbilical and middle cerebral arteries Doppler indices showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = .001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value = .001).Conclusions: Sildenafil citrate may improve uteroplacental and fetal cerebral perfusion in pregnancies complicated by severe intrauterine growth restriction. It also improves abdominal circumference growth velocity. A wide scale randomized trials are needed for evaluation of neonatal and long term morbidity and mortality outcomes of pregnancies treated by sildenafil citrate.

Maternal omega-3 fatty acids and vitamin E improve placental angiogenesis in late-onset but not early-onset preeclampsia.

Abnormal placental vasculature is associated with preeclampsia. Preeclampsia is of two types, i.e., early- and late-onset preeclampsia (LOP), both having different etiologies. We have earlier demonstrated low levels of omega-3 fatty acids and vitamin E in women with preeclampsia. The current study examines the effect of maternal omega-3 fatty acids and vitamin E supplementation on angiogenic factors in a rat model of preeclampsia. Pregnant rats were divided into a total of five groups control, early-onset preeclampsia (EOP); LOP; EOP supplemented with omega-3 fatty acid and vitamin E and LOP supplemented with omega-3 fatty acid and vitamin E. Preeclampsia was induced by administering L-nitroarginine methylester (L-NAME) at the dose of 50 mg/kg body weight/day. The vascular endothelial growth factor gene expression and protein levels were lower (p < 0.01 for both) in animals from both EOP as well as LOP groups (p < 0.01). In the EOP group, the protein levels of VEGF receptor-1 were also lower (p < 0.01). Supplementation of omega-3 fatty acids and vitamin E to LOP improved the levels of VEGF and VEGF receptor-1 only in the LOP but not in the EOP group. In the EOP group, the gene expression of hypoxia inducible factor 1 alpha (HIF-1α) in the placenta was higher (p < 0.05) and supplementation normalized these levels. Our findings indicate that maternal supplementation of omega-3 fatty acids and vitamin E has differential effect on preeclampsia subtypes.

Perspective: L-arginine and L-citrulline Supplementation in Pregnancy: A Potential Strategy to Improve Birth Outcomes in Low-Resource Settings.

The available data support the hypothesis that L-arginine or L-citrulline supplementation would be suitable for implementation in resource-constrained settings and will enhance placental vascular development and improve birth outcomes. In resource-constrained settings, the rates of adverse birth outcomes, including fetal growth restriction, preterm birth, and low birth weight, are disproportionately high. Complications resulting from preterm birth are now the leading cause of mortality in children <5 y of age worldwide. Despite the global health burden of adverse birth outcomes, few effective interventions are currently available and new strategies are urgently needed, especially for low-resource settings. L-arginine is a nutritionally essential amino acid in pregnancy and an immediate precursor of nitric oxide. During pregnancy, placental and embryonic growth increases the demand for L-arginine, which can exceed endogenous synthesis of L-arginine from L-citrulline, necessitating increased dietary intake. In many low-resource settings, dietary intake of L-arginine in pregnancy is inadequate owing to widespread protein malnutrition and depletion of endogenous L-arginine due to maternal infections, in particular malaria. Here we examine the role of the L-arginine-nitric oxide biosynthetic pathway in pregnancy including placental vascular development and fetal growth. We review the evidence for the relations between altered L-arginine bioavailability and pregnancy outcomes, and strategies for arginine supplementation in pregnancy. Existing studies of L-arginine supplementation in pregnancy in high-resource settings have shown improved maternal and fetal hemodynamics, prevention of pre-eclampsia, and improved birth outcomes including higher birth weight and longer gestation. Arginine supplementation studies now need to be extended to pregnant women in low-resource settings, especially those at risk of malaria.

Fully automatic 3D reconstruction of the placenta and its peripheral vasculature in intrauterine fetal MRI.

Recent advances in fetal magnetic resonance imaging (MRI) open the door to improved detection and characterization of fetal and placental abnormalities. Since interpreting MRI data can be complex and ambiguous, there is a need for robust computational methods able to quantify placental anatomy (including its vasculature) and function. In this work, we propose a novel fully-automated method to segment the placenta and its peripheral blood vessels from fetal MRI. First, a super-resolution reconstruction of the uterus is generated by combining axial, sagittal and coronal views. The placenta is then segmented using 3D Gabor filters, texture features and Support Vector Machines. A uterus edge-based instance selection is proposed to identify the support vectors defining the placenta boundary. Subsequently, peripheral blood vessels are extracted through a curvature-based corner detector. Our approach is validated on a rich set of 44 control and pathological cases: singleton and (normal / monochorionic) twin pregnancies between 25-37 weeks of gestation. Dice coefficients of 0.82 â€¯±â€¯ 0.02 and 0.81 â€¯±â€¯ 0.08 are achieved for placenta and its vasculature segmentation, respectively. A comparative analysis with state of the art convolutional neural networks (CNN), namely, 3D U-Net, V-Net, DeepMedic, Holistic3D Net, HighRes3D Net and Dense V-Net is also conducted for placenta localization, with our method outperforming all CNN approaches. Results suggest that our methodology can aid the diagnosis and surgical planning of severe fetal disorders.

Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth.

Foals born to primiparous mares are lighter and less mature than those born to multiparous dams. Factors driving this difference are not totally understood. Using 7 multiparous and 6 primiparous standardbred mares, we demonstrated that, in late gestation, primiparous mares were less insulin resistant compared to multiparous mares, and that their foals had reduced plasma amino-acid concentrations at birth compared to foals born to multiparous mares. Vascular development, as observed through structure and gene expression, and global DNA methylation were also reduced in primiparous placentas. Another group of 8 primiparous mares was orally supplemented with L-arginine (100 g/day, 210d to term). L-arginine improved pregnancy-induced insulin resistance and increased maternal L-arginine and L-ornithine plasma concentrations but foal plasma amino acid concentrations were not affected at birth. At birth, foal weight and placental biometry, structure, ultra-structure and DNA methylation were not modified. Placental expression of genes involved in glucose and fatty acid transfers was increased. In conclusion, maternal insulin resistance in response to pregnancy and placental function are reduced in primiparous pregnancies. Late-gestation L-arginine supplementation may help primiparous mares to metabolically adapt to pregnancy and improve placental function. More work is needed to confirm these effects and ascertain optimal treatment conditions.

Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts.

Gestational diabetes mellitus (GDM) is characterized by excessive placental fat and glucose transport, resulting in fetal overgrowth. Earlier we demonstrated that maternal choline supplementation normalizes fetal growth in GDM mice at mid-gestation. In this study, we further assess how choline and its oxidation product betaine influence determinants of placental nutrient transport in GDM mice and human trophoblasts. C57BL/6J mice were fed a high-fat (HF) diet 4 weeks prior to and during pregnancy to induce GDM or fed a control normal fat (NF) diet. The HF mice also received 25 mM choline, 85 mM betaine, or control drinking water. We observed that GDM mice had an expanded placental junctional zone with an increased area of glycogen cells, while the thickness of the placental labyrinth zone was decreased at E17.5 compared to NF control mice (p < 0.05). Choline and betaine supplementation alleviated these morphological changes in GDM placentas. In parallel, both choline and betaine supplementation significantly reduced glucose accretion (p < 0.05) in in vitro assays where the human choriocarcinoma BeWo cells were cultured in high (35.5 mM) or normal (5.5 mM) glucose conditions. Expression of angiogenic genes was minimally altered by choline or betaine supplementation in either model. In conclusion, both choline and betaine modified some but not all determinants of placental transport in response to hyperglycemia in mouse and in vitro human cell line models.

Effect of chronic melatonin supplementation during mid to late gestation on maternal uterine artery blood flow and subsequent development of male offspring in beef cattle.

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.

An effect of maternal nifedipine therapy on fetoplacental blood flow: a prospective study.

PURPOSE: The aim of this study is to assess the effects of maternal nifedipine administration on placental and fetal blood flow. METHODS: A total of 29 patients with preterm labor diagnosis admitted to the tertiary care center, Zeynep Kamil Hospital, were evaluated. Before and 24-48 h after administration of oral nifedipine, Doppler ultrasound scan was carried out to measure fetal middle cerebral artery, ductus venosus, umbilical artery, and maternal uterine artery blood flow. RESULTS: After 24 and 48 h of therapy, there were no changes in mean PI and RI in the umbilical arteries and ductus venosus (p > 0.05). Fetal middle cerebral artery and maternal uterine artery PI and RI values showed a significant reduction 24-48 h after oral nifedipine therapy (p < 0.05). CONCLUSIONS: Our study showed that 24 and 48 h after oral nifedipine therapy, there is a significant increase in fetal MCA and maternal uterine artery blood flow, while fetal umbilical artery and ductus venosus Doppler values do not change.

Ex Vivo Dual Perfusion of the Human Placenta: Disease Simulation, Therapeutic Pharmacokinetics and Analysis of Off-Target Effects.

In recent years ex vivo dual perfusion of the human placental lobule is seeing an international renaissance in its application to understanding fetal health and development. Here, we discuss the methods and uses of this technique in the evaluation of (1) vascular function, (2) transplacental clearance, (3) hemodynamic and oxygenation changes associated with pregnancy complications on placental structure and function, and (4) placental toxicology and post-perfusion evaluation of tissue architecture.

Vitamin D Supplementation Prevents Placental Ischemia Induced Endothelial Dysfunction by Downregulating Placental Soluble FMS-Like Tyrosine Kinase-1.

Maternal vitamin D deficiency in pregnancy has been associated with an increased risk of preeclampsia. Vascular endothelial dysfunction is a major phenotype of pregnancies with preeclampsia, contributing to increased maternal hypertension and proteinuria. We sought to determine whether vitamin D supplementation would alleviate preeclampsia associated endothelial dysfunction and explore the underlying mechanism using the reduced uterine perfusion pressure (RUPP) rat model. RUPP operated rats were supplemented with 1,25(OH)2D (RUPP+VD) on day 1, 7, and 14 of pregnancy by subcutaneous injection. On day 19 of pregnancy, after the measurement of blood pressure and urine collection, maternal blood serum and placenta samples were collected. 1,25(OH)2D treatment significantly improved endothelial dysfunction by reducing apoptosis and increasing nitric oxide (NO) production in blood vessels of RUPP operated rats compared to untreated RUPP rats. 1,25(OH)2D significantly down-regulated the expression of placental soluble FMS-like tyrosine kinase-1 (sFlt-1) in RUPP rats. Furthermore, the circulating sFlt-1 levels in maternal serum were positively correlated with the expression of placental sFlt-1 and were restored to a normal pregnant level by 1,25(OH)2D treatment in RUPP rats. Incubation of endothelial cell line with rat serum from RUPP+VD group significantly increased NO production and decreased caspase-3 activity compared with serum from untreated RUPP rats. Moreover, neutralization of sFlt-1 using the specific antibody mimicked the effect of 1,25(OH)2D, which abolished the deleterious effect of RUPP rat's serum on NO production and apoptosis. These results suggest that vitamin D supplementation is protective against RUPP induced endothelial dysfunction by downregulating placental sFlt-1, which can possibly alleviate preeclampsia associated symptoms.

PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Alterations in uteroplacental hemodynamics during melatonin supplementation in sheep and cattle.

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. The amplitude of melatonin secretion has been associated with improved oxidative status and altered cardiovascular function in several mammalian species; however, melatonin mediated alterations of uteroplacental capacity in sheep and cattle are lacking. Therefore, our laboratories are examining uteroplacental blood flow and fetal development during maternal melatonin supplementation. Using a mid- to late-gestation ovine model of intrauterine growth restriction, we examined uteroplacental blood flow and fetal growth during supplementation with 5 mg/d of dietary melatonin. Maternal nutrient restriction decreased uterine arterial blood flow, while melatonin supplementation increased umbilical arterial blood flow compared with non-supplemented controls. Although melatonin treatment did not rescue fetal weight in nutrient restricted ewes; we observed disproportionate fetal size and fetal organ development. Elevated fetal concentrations of melatonin may result in altered blood flow distribution during important time points of development. These melatonin specific responses on umbilical arterial hemodynamics and fetal development may be partially mediated through vascular melatonin receptors. Recently, we examined the effects of supplementing Holstein heifers with 20 mg/d of dietary melatonin during the last third of gestation. Uterine arterial blood flow was increased by 25% and total serum antioxidant capacity was increased by 43% in melatonin supplemented heifers vs. 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 hormonal supplements on the continual plasticity of placental function will allow us to determine important endogenous mediators of offspring growth and development.