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Fetal growth restriction (FGR) and stillbirth are associated with placental dysfunction and inflammation and hypoxia, oxidative and nitrative stress are implicated in placental damage. Damage-associated molecular patterns (DAMPs) are elevated in pregnancies at increased risk of FGR and stillbirth and are associated with increase in pro-inflammatory placental cytokines. We hypothesised that placental insults lead to release of DAMPs, promoting placental inflammation. Placental tissue from uncomplicated pregnancies was exposed in vitro to hypoxia, oxidative or nitrative stress. Tissue production and release of DAMPs and cytokines was determined. Oxidative stress and hypoxia caused differential release of DAMPs including uric acid, HMGB1, S100A8, cell-free fetal DNA, S100A12 and HSP70. After oxidative stress pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, TNFα, CCL2) were increased both within explants and in conditioned culture medium. Hypoxia increased tissue IL-1α/β, IL-6, IL-8 and TNFα levels, and release of IL-1α, IL-6 and IL-8, whereas CCL2 and IL-10 were reduced. IL1 receptor antagonist (IL1Ra) treatment prevented hypoxia- and oxidative stress-induced IL-6 and IL-8 release. These findings provide evidence that relevant stressors induce a sterile inflammatory profile in placental tissue which can be partially blocked by IL1Ra suggesting this agent has translational potential to prevent placental inflammation evident in FGR and stillbirth.

Fetal growth restriction (FGR), where a fetus fails to reach its genetic growth potential, affects up to 8% of pregnancies and is a major risk factor for stillbirth and adulthood morbidity. There are currently no treatments for FGR, but candidate therapies include the phosphodiesterase-5 inhibitor sildenafil citrate (SC). Randomized clinical trials in women demonstrated no effect of SC on fetal growth in cases of severe early onset FGR; however, long-term health outcomes on the offspring are unknown. This study aimed to assess the effect of antenatal SC treatment on metabolic and cardiovascular health in offspring by assessing postnatal weight gain, glucose tolerance, systolic blood pressure, and resistance artery function in a mouse model of FGR, the placental-specific insulin-like growth factor 2 (PO) knockout mouse. SC was administered subcutaneously (10 mg/kg) daily from embryonic day (E)12.5. Antenatal SC treatment did not alter fetal weight or viability but increased postnatal weight gain in wild-type (WT) female offspring ( P < 0.05) and reduced glucose sensitivity in both WT ( P < 0.01) and P0 ( P < 0.05) female offspring compared with controls. Antenatal SC treatment increased systolic blood pressure in both male (WT vs. WT-SC: 117 ± 2 vs. 140 ± 3 mmHg, P < 0.0001; P0 vs. P0-SC: 113 ± 3 vs. 140 ± 4 mmHg, P < 0.0001; means ± SE) and female (WT vs. WT-SC: 121 ± 2 vs. 140 ± 2 mmHg, P < 0.0001; P0 vs. P0-SC: 117 ± 2 vs. 144 ± 4 mmHg, P < 0.0001) offspring at 8 and 13 wk of age. Increased systolic blood pressure was not attributed to altered mesenteric artery function. In utero exposure to SC may result in metabolic dysfunction and elevated blood pressure in later life. NEW & NOTEWORTHY Sildenafil citrate (SC) is currently used to treat fetal growth restriction (FGR). We demonstrate that SC is ineffective at treating FGR, and leads to a substantial increase systolic blood pressure and alterations in glucose homeostasis in offspring. We therefore urge caution and suggest that further studies are required to assess the safety and efficacy of SC in utero, in addition to the implications on long-term health.

Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Background/objectives: Maternal obesity increases the risk of poor pregnancy outcome including stillbirth, pre-eclampsia, fetal growth restriction and fetal overgrowth. These pregnancy complications are associated with dysfunctional syncytiotrophoblast, the transporting epithelium of the human placenta. Taurine, a β-amino acid with antioxidant and cytoprotective properties, has a role in syncytiotrophoblast development and function and is required for fetal growth and organ development. Taurine is conditionally essential in pregnancy and fetal tissues depend on uptake of taurine from maternal blood. We tested the hypothesis that taurine uptake into placental syncytiotrophoblast by the taurine transporter protein (TauT) is lower in obese women (body mass index (BMI)⩾30 kg m(-)(2)) than in women of ideal weight (BMI 18.5-24.9 kg m(-)(2)) and explored potential regulatory factors., Subjects/methods: Placentas were collected from term (37-42-week gestation), uncomplicated, singleton pregnancies from women with BMI 19-49 kg m(-)(2). TauT activity was measured as the Na(+)-dependent uptake of (3)H-taurine into placental villous fragments. TauT expression in membrane-enriched placental samples was investigated by western blot. In vitro studies using placental villous explants examined whether leptin or IL-6, adipokines/cytokines that are elevated in maternal obesity, regulates TauT activity., Results: Placental TauT activity was significantly lower in obese women (BMI⩾30) than women of ideal weight (P<0.03) and inversely related to maternal BMI (19-49 kg m(-)(2); P<0.05; n=61). There was no difference in TauT expression between placentas of ideal weight and obese class III (BMI⩾40) subjects. Long-term exposure (48 h) of placental villous explants to leptin or IL-6 did not affect TauT activity., Conclusions: Placental TauT activity at term is negatively related to maternal BMI. We propose that the reduction in placental TauT activity in maternal obesity could lower syncytiotrophoblast taurine concentration, compromise placental development and function, and reduce the driving force for taurine efflux to the fetus, thereby increasing the risk of poor pregnancy outcome.

Objectives: Previous work suggests an association between air pollution exposure and adverse pregnancy outcomes, even at relatively low concentrations. Our aim was to quantify the effect of air pollution having an adverse effect on preterm birth (PTB) and fetal growth in a large UK cohort using a novel exposure estimation technique [spatio-temporal (S-T) model] alongside a traditional nearest stationary monitor technique (NSTAT)., Methods: All available postcodes from a Northwest England birth outcome dataset during 2004-2008 were geocoded (N=203 562 deliveries). Pollution estimates were linked to corresponding pregnancy periods using temporally adjusted background modelled concentrations as well as NSTAT. Associations with PTB, small for gestational age (SGA), and birth weight were investigated using regression models adjusting for maternal age, ethnicity, parity, birth season, socioeconomic status (SES), body mass index (BMI), and smoking., Results: Based on the novel S-T model, a small statistically significant association was observed for particulate matter (PM10) and SGA, particularly with exposure in the first and third trimesters. Similar effects on SGA were also found for nitrogen dioxide (NO 2), particulate matter (PM 2,5), and carbon monoxide (CO) in later pregnancy, but no overall increased risk was observed. No associations were found with NO xor the outcomes PTB and reduction in birth weight., Conclusion: Our findings suggest an association between air pollution exposure and birth of a SGA infant, particularly in the later stages of pregnancy but not with PTB or mean birth weight change.

The outer epithelial cell layer of human placenta, the syncytiotrophoblast, is a specialised terminally differentiated multinucleate tissue. It is generated and renewed from underlying cytotrophoblast cells that undergo proliferation, differentiation and fusion with syncytiotrophoblast. Acquisition of fresh cellular components is thought to be balanced by apoptosis and shedding of aged nuclei. This process of trophoblast cell turnover maintains a functional syncytiotrophoblast, capable of sufficient nutrient transfer from mother to foetus. Foetal growth restriction (FGR) is a pregnancy complication associated with aberrant trophoblast turnover and reduced activity of certain amino acid transporters, including the taurine transporter (TauT). Taurine is the most abundant amino acid in human placenta implying an important physiological role within this tissue. Unlike other amino acids, taurine is not incorporated into proteins and in non-placental cell types represents an important osmolyte involved in cell volume regulation, and is also cytoprotective. Here, we investigated the role of taurine in trophoblast turnover using RNA interference to deplete primary human trophoblast cells of TauT and reduce intracellular taurine content. Trophoblast differentiation was compromised in TauT-deficient cells, and susceptibility of these cells to an inflammatory cytokine that is elevated in FGR was increased, evidenced by elevated levels of apoptosis. These data suggest an important role for taurine in trophoblast turnover and cytoprotection.

Fetal growth restriction (FGR) is a serious pregnancy complication, resulting in significant perinatal morbidity and mortality. Increased vascular resistance in the fetoplacental circulation is a hallmark of FGR and is associated with enhanced vasoconstriction of the resistance arteries in the placenta, the chorionic plate arteries (CPAs). Although the cause is unknown, FGR is associated with excess exposure to glucocorticoids (GCs), key mediators of vascular resistance in the systemic circulation. We hypothesized that GCs alter CPA reactivity, thereby contributing to the altered blood flow dynamics seen in FGR. We aimed to examine the acute and chronic effects of GCs on CPA reactivity and the operational mechanisms. Glucocorticoid receptors were highly expressed by CPA. 11β-Hydroxysteroid isoenzyme type 2 was detected within the endothelium, whereas 11β-hydroxysteroid isoenzyme type 1 was absent. Acute GC treatment significantly attenuated U46619-induced constriction. This effect was reversed by cotreatment with mifepristone or an endothelial NOS inhibitor. In contrast, chronic GC treatment potentiated U46619 constriction in a dose-dependent manner, which was partially abolished by mifepristone cotreatment. Similar effects were observed using a novel nonsteroidal glucocorticoid receptor-specific agonist. Chronic treatment with GCs altered the expression of several vasoactive factors, including thromboxane and bradykinin receptors, prokineticin-1, cyclooxygenase-2, and endothelial NOS. In summary, acute and chronic GC treatment exerts contrasting effects on CPA vasoreactivity. These opposing effects are consistent with temporal actions in other vascular beds and reflect activation of distinct nongenomic and genomic pathways. Chronic exposure to elevated GCs may contribute to the raised vascular resistance observed in the fetoplacental circulation in FGR.

We tested the hypothesis that crossing two mouse models of fetal growth restriction (FGR) of differing phenotype would induce more severe FGR than either model alone. Female endothelial nitric oxide synthase knockout mice (eNOS(-/-)) were mated with placental-specific Igf2 knockout males (P0). Resultant fetuses were no more growth restricted than those with P0 deletion alone. However, P0 deletion attenuated the reduced placental system A amino acid transporter activity previously observed in eNOS(-/-) mice. Manipulating maternal and fetal genotypes provides a means to compare maternal and fetal regulation of fetal growth., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Unlabelled: Placental insufficiency is a major cause of fetal growth restriction (FGR) and accumulating evidence indicates several aspects of placental morphology are altered in this condition. MRI provides quantitative indices that may be used in non-invasive assessment of the human placenta, such as relaxation time measurements, T1 and T2. We hypothesised that placental relaxation times relate to alterations in placental tissue morphology and hence may be useful in identifying the changes associated with FGR. We report on the first phase of testing this hypothesis, in a study of women in normal pregnancy., Aims: To assess relaxation time measurements in the placenta in normal pregnancy and correlate these with gestational age and stereological analyses of placental morphology following delivery., Methods: 30 women underwent MRI examination (1.5 T) between 20 and 41 weeks gestation. Placental T1 and T2 measurements were acquired from a mid-depth placental region, co-localised to a structural scan. Fixed, wax-embedded sections of these placentas collected at delivery were stained with hematoxylin/eosin and subjected to stereological analysis., Results: Placental T1 and T2 show a significant negative correlation with gestation, (Pearson correlation p=0.01, 0.03 respectively). 17 placentas were analysed stereologically. In the group as a whole there was no significant correlation between T1 and T2 and morphological features. However, in a subset of 7 pregnancies scanned within a week of delivery, a significant positive correlation was observed between the fibrin volume density and the ratio of fibrin: villous volume densities and T2 (Spearman correlation p=0.02, 0.03 respectively)., Discussion: The correlations between placental T1 and T2 and gestation show that these variables are clearly influenced by changes in placental structure. Fibrin might be a key component but further work is needed to fully elucidate the major structural influences on placental T1 and T2., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The increasing number of mouse models of fetal growth restriction (FGR) make it crucial to standardize the way FGR is defined. By constructing growth curves in the placental-specific Igf2 knockout mouse (P0) it was demonstrated that 93% of P0 fetuses fell below the 5th centile of wild-type weights at E18.5, up from 44% at E16.5. This analysis, coupled with anthropomorphic measurements showing evidence of head sparing in P0 fetuses, allows clinical comparisons of FGR in mice through the use of clinically relevant growth curves. We suggest this as a standardized approach to defining FGR in mouse, and other animal models., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Evidence is emerging that the ability of the placenta to supply nutrients to the developing fetus adapts according to fetal demand. To examine this adaptation further, we tested the hypothesis that placental maternofetal transport of calcium adapts according to fetal calcium requirements. We used a mouse model of fetal growth restriction, the placental-specific Igf2 knockout (P0) mouse, shown previously to transiently adapt placental System-A amino acid transporter activity relative to fetal growth. Fetal and placental weights in P0 mice were reduced when compared with WT at both embryonic day 17 (E17) and E19. Ionized calcium concentration [Ca(2+)] was significantly lower in P0 fetal blood compared with both WT and maternal blood at E17 and E19, reflecting a reversal of the fetomaternal [Ca(2+)] gradient. Fetal calcium content was reduced in P0 mice at E17 but not at E19. Unidirectional maternofetal calcium clearance ((Ca) K (mf)) was not different between WT and P0 at E17 but increased in P0 at E19. Expression of the intracellular calcium-binding protein calbindin-D(9K), previously shown to be rate-limiting for calcium transport, was increased in P0 relative to WT placentas between E17 and E19. These data show an increased placental transport of calcium from E17 to E19 in P0 compared to WT. We suggest that this is an adaptation in response to the reduced fetal calcium accumulation earlier in gestation and speculate that the ability of the placenta to adapt its supply capacity according to fetal demand may stretch across other essential nutrients.

The placenta, in general and the physiology of maternofetal nutrient transfer is under-researched compared to other organs with epithelial transport function, as evidenced, for example, by publication numbers. This report provides reasons why more researchers should become involved in this topic. First, the syncytiotrophoblast, the transporting epithelium of the placenta, though having many basic cell physiology properties similar to those of other transporting epithelia, has several properties which are markedly different. Better information on these might help fundamental understanding of how epithelia in general function as well as improving knowledge of how the syncytiotrophoblast operates. Second, the synctiotrophoblast has a key role in controlling fetal growth, not only by transporting nutrients and waste products of metabolism but also because it increasingly appears to be one site, perhaps even the dominant site, in which integration of, sometimes conflicting, signals between mother and fetus takes place. Finally, better understanding of placental nutrient transfer and especially of how it is regulated by maternal and fetal signals could provide better information on the placental phenotype in fetal growth disorders--information which might contribute to providing better biomarkers which the obstetrician could use to improve early diagnosis of these disorders.

Regulation of syncytiotrophoblast intracellular pH is critical to optimum enzymatic and transport functions of the placenta. Previous studies of Na(+)/H(+) exchanger (NHE) activity in the placenta from pregnancies complicated by intrauterine growth restriction (IUGR) have produced conflicting results. The possible role of altered placental pH regulation in the development of acidosis in some fetuses subjected to IUGR remains to be fully established. We investigated the activity and protein expression of the NHE in syncytiotrophoblast microvillous (MVM) plasma membranes isolated from preterm and term placentas obtained from uncomplicated and IUGR pregnancies. Western blotting showed that the expression of NHE isoforms 1, 2, and 3 was approximately 10-fold greater in MVM than in basal plasma membrane (BM). Immunohistochemistry localized NHE-1 and NHE-2 to MVM and BM and NHE-3 to the MVM, BM, and cytoplasm of the syncytiotrophoblast. NHE-1 expression in MVM from preterm IUGR placentas was reduced by 55%, compared with gestational age-matched controls (P < 0.05, n = 6 and n = 16, respectively), whereas NHE-1 expression was unaltered in term IUGR placentas (n = 8). The activity (amiloride-sensitive Na(+) uptake) of NHE in MVM from IUGR preterm placentas was reduced by 48% (P < 0.05, n = 6). In contrast, MVM NHE activity was unchanged in term IUGR (n = 7). Using Northern blotting, no difference could be demonstrated in NHE-1 mRNA expression between IUGR and control groups. The reduced activity and expression of NHE in MVM of preterm IUGR placentas may compromise placental function and may contribute to the development of fetal acidosis in preterm IUGR fetuses.

Primarily, our objectives were to compare system A amino acid transporter activity in the microvillous plasma membrane (MVM) of placentas from normally grown (appropriate for gestational age, AGA) and intrauterine growth-restricted (IUGR) fetuses delivered during the third trimester, as a whole and in relation to the severity of IUGR. Ten AGA and 16 IUGR pregnancies were studied at the time of elective cesarean section performed between 28 and 40 wk of gestation. Severity of IUGR pregnancies was assessed primarily by Doppler velocimetry and fetal heart rate monitoring. Placental MVM vesicles were prepared, and system A activity in these was measured. The transporter activity was significantly lower in IUGR compared with AGA pregnancies. Within the IUGR group system A activity was only significantly lower, compared with AGA, in cases that presented with a reduction in umbilical blood flow. We conclude that placental MVM system A activity is lower in IUGR compared with AGA pregnancies delivered during the third trimester. System A activity is related to the severity of IUGR.

To determine whether reduced maternofetal transfer of neutral amino acids in growth-restricted fetal rats is due to decreased system A transporter activity, we measured Na(+)-dependent MeAIB uptake by membrane vesicles from placentas of fetuses growth-restricted due to uterine artery ligation and control placentas (sham ligation). Na(+)-dependent uptake of methylamino-isobutyric acid (MeAIB) was linear over 15-60 s in vesicles from both ligated and sham-ligated sides of the uterus. Na(+)-dependent uptake of MeAIB at 30 s did not differ in paired measurements on vesicles from ligated and sham-ligated horns, 0.063 +/- 0.004 versus 0.056 +/- 0.005 nmol/mg of vesicle protein. The kinetics of Na(+)-dependent MeAIB uptake were similar in paired measurements on vesicles from ligated and sham-ligated horns, with overall K(m) = 4.4 +/- 0.5 mM and Vmax = 0.93 +/- 0.08 nmol/mg vesicle protein per 30 s. Uptake of tracer was inhibited 85-95% by known substrates for the system A amino acid transporter (alanine > or = serine > MeAIB > glycine = proline). We conclude that the system A transporter is present in the maternal facing plasma membrane of rat syncytiotrophoblast, but that the activity of this system, per mg of vesicle protein, is unaffected in fetal growth restriction induced by a decrease in maternal placental blood flow in late pregnancy.

Fetal growth restriction (FGR) is defined as the failure of a fetus to attain its full genetic growth potential. It is a leading cause of stillbirth, prematurity, cerebral palsy and perinatal mortality. Small size at birth increases surviving infants’ lifelong risk of adverse health outcomes associated with the metabolic syndrome. The pathophysiology of abnormal fetal growth is extremely complex and incompletely understood, with a plethora of genetic, signalling and metabolic candidates under investigation, many of which may result in abnormal structure and function of the placenta. In contrast to, or maybe because of, the underlying complexities of FGR, the strategies clinicians have for identifying and managing this outcome are conspicuously limited. Current clinical practice is restricted to identifying pregnancies at risk of FGR, and when FGR is detected, using intensive monitoring to guide the timing of delivery to optimise fetal outcomes. Abnormal Doppler indices in the umbilical artery are strongly associated with poor perinatal outcomes and are currently the “gold standard” for clinical surveillance of the growth-restricted fetus. [ABSTRACT FROM AUTHOR]

Adequate blood flow provision through alterations in maternal vascular function is essential during pregnancy for optimal fetal development. Abnormal uterine vasculature adaptation, resulting in aberrant blood flow to the placenta, has been implicated as a possible cause of fetal growth restriction (FGR). Our study aimed to develop strategies to evaluate murine vascular function in pregnancy using wire myography. Main uterine artery loop and branch vessels isolated from near-term pregnant mice showed significant contraction to phenylephrine (PE). Endothelial-dependent relaxation was noted with acetylcholine (ACH). U46619 elicited significant contraction of umbilical arteries and veins, but relaxation was only demonstrable with the nitric oxide (NO) donor sodium nitroprusside (SNP). In conclusion, our data suggest that murine uteroplacental and fetoplacental arteries show distinct responses to vasoactive agents. Furthermore, this study indicates that wire myography represents a robust technique for the assessment of murine uteroplacental and fetoplacental vascular function, which will aid evaluation of mouse genetic models of FGR. [ABSTRACT FROM AUTHOR]

Since the advent of technologies to produce genetic knockout and transgenic mice, the number of mouse strains suggested to be useful as models for pregnancy-related complications in the human has risen substantially. Some of these share features in common with fetal growth restriction (FGR) and preeclampsia (PE) and could be useful for investigating aetiologies and for testing potential therapeutics to improve outcome in these diseases. However, since placental pathology is a major underlying factor in both FGR and PE, it is important to understand the similarities and differences in structure and function of the placenta between mice and women. The main aim of this review is to directly compare placental exchange physiology between human and mouse. The review will compare human and mouse in both normal and pathological circumstances, to attempt to answer the question of whether placental studies in the mouse can be translated to the human. The review includes descriptions of placental structure between the species, comparisons of nutrient transport, including amino acids, glucose and calcium, and evidence of how these transport systems are altered in both human FGR and mouse models of this disease. Finally, our review will conclude by examining studies in which mouse models of FGR/PE have been treated with drugs of potential therapeutic value in women and consider whether data obtained in mice can be a prelude for clinical trials in human. [ABSTRACT FROM AUTHOR]