Pharmacological management of an impending placental insufficiency

By means of drug administration a further decrease of the placental circulation in premature sonographic maturity of the placenta could be prevented via influencing the TXA2/PGI2 balance. Treatment of premature sonographic placental maturity with 50 mg acetylsalicylic acid (ASA) per day and three times daily 100 mg Rocornal, respectively, resulted in a significant increase of the birth weights. In a second series of experiments, three groups were treated with 50 mg/day ASA or 250 mg ASA/once per week and three times/day 100 mg Rocornal, respectively, from the 18th or 20th week of gestation to the 35th week. Subsequently, they were compared to a group of untreated controls. The birth weights of all treated groups were statistically significantly higher. The underlying mechanism is suggested to be an improved microcirculation.     

Pregnancy-associated venous insufficiency course with placental and systemic oxidative stress

The development of lower extremity venous insufficiency (VI) during pregnancy has been associated with placental damage. VI is associated with increased oxidative stress in venous wall. We have investigated potential disturbance/dysregulation of the production of reactive oxygen species (ROS) in placenta and its eventual systemic effects through the measurement of malondialdehyde (MDA) plasma levels in women with VI. A total of 62 women with VI and 52 healthy controls (HCs) were studied. Levels of nicotinamide adenine dinucleotide phosphate-oxidase 1 (NOX1), 2 (NOX2), inducible nitric oxide synthase (iNOS), endothelial (eNOS), poly(ADP-ribose) polymerase PARP (PARP) and ERK were measured in placental tissue with immunohistochemistry and RT-qPCR. Plasma and placental levels of MDA were determined by colorimetry at the two study times of 32 weeks of gestation and post-partum. Protein and gene expression levels of NOX1, NOX2, iNOS, PARP and ERK were significantly increased in placentas of VI. eNOS activity was low in both study groups, and there were no significant differences in gene or protein expression levels. Women with VI showed a significant elevation of plasma MDA levels at 32 weeks of gestation, and these levels remained elevated at 32 weeks post-partum. The MDA levels were significantly higher in placentas of women with VI. Placental damage that was found in the women with VI was characterized by overexpression of oxidative stress markers NOX1, NOX2, and iNOS, as well as PARP and ERK. Pregnant women with VI showed systemic increases in oxidative stress markers such as plasma MDA levels. The foetuses of women with VI had a significant decrease in their venous pH as compared to those from HC women. The situation of oxidative stress and cellular damage created in the placenta is in coexpression with the production of a pH acidification.     

Comparative proteomic analysis associated with term placental insufficiency in cloned pig

Somatic cell-derived nuclear transfer (scNT) is a method of animal cloning in which the oocyte reprograms a somatic cell nucleus to divide and execute developmental programs. Despite many successes in this field, cloning by scNT remains very inefficient. Unlike other cloned animals, pigs derived by scNT have placentas with severe villous hypoplasia. To obtain a better understanding of the protein networks involved in this phenomenon, we assessed global protein expression profiles in term placentas from scNT-derived and control animals. Proteomic analysis of term placentas from scNT-derived animals identified 43 proteins that were differentially expressed compared to control animals. Among them, 14-3-3 proteins and Annexin V, which are closely involved in the apoptotic signaling pathway, were significantly down- and up-regulated, respectively. Western blot analysis and immunohistochemistry indicated that down-regulation of 14-3-3 proteins in scNT-derived placentas induced apoptosis of cytotrophoblast cells via mitochondria-mediated apoptosis. Taken together, our results suggest that placental insufficiency in scNT-derived placentas may be due to apoptosis, induced in part by the down-regulation of 14-3-3 proteins and up-regulation of Annexin V. They also indicate that proteomic maps represent an important tool for future studies of placental insufficiency and pathology.     

Extracellular nucleic acids in maternal circulation as potential biomarkers for placental insufficiency

Since the placenta is being continuously remodeled during normal placental development, extracellular nucleic acids of both fetal and placental origin, packed into either trophoblast-derived apoptotic bodies or shedding syncytiotrophoblast microparticles, may be detected in maternal circulation during the course of normal gestation. Placental-insufficiency-related pregnancy complications have been shown to be associated with excessive placental trophoblast apoptosis and shedding of placenta debris. Recent advances in the field are reviewed with a focus on the diagnostic potential of particular molecular biomarkers and their eventual implementation in the currently used predictive and diagnostic algorithms for placental-insufficiency-related pregnancy complications.     

Status and reaction to anoxia of rat fetuses developing in conditions of placental insufficiency

Significant adverse correlation of the fetus mass and the degree of its hydration was noted at term in rats with placental insufficiency induced by ligation of about 40% of preplacental vessels on the 16th day of gestation. Disorders revealed in transplacental water-salt metabolism are apparently of some importance for the pathogenesis of fetal growth retardation. Even moderate retardation alters fetal respiratory activity in anoxia, which is associated with the changes in the function of respiratory centres and neuromuscular abnormalities.     

Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction

In this study we determined body weight-specific fetal (umbilical) glucose uptake (UGU), utilization (GUR), and production rates (GPR) and insulin action in intrauterine growth-restricted (IUGR) fetal sheep. During basal conditions, UGU from the placenta was 33% lower in IUGR fetuses, but GUR was not different between IUGR and control fetuses. The difference between glucose utilization and UGU rates in the IUGR fetuses demonstrated the presence and rate of fetal GPR (41% of GUR). The mRNA concentrations of the gluconeogenic enzymes glucose-6-phophatase and PEPCK were higher in the livers of IUGR fetuses, perhaps in response to CREB activation, as phosphorylated CREB/total CREB was increased 4.2-fold. A hyperglycemic clamp resulted in similar rates of glucose uptake and utilization in IUGR and control fetuses. The nearly identical GURs in IUGR and control fetuses at both basal and high glucose concentrations occurred at mean plasma insulin concentrations in the IUGR fetuses that were approximately 70% lower than controls, indicating increased insulin sensitivity. Furthermore, under basal conditions, hepatic glycogen content was similar, skeletal muscle glycogen was increased 2.2-fold, the fraction of fetal GUR that was oxidized was 32% lower, and GLUT1 and GLUT4 concentrations in liver and skeletal muscle were the same in IUGR fetuses compared with controls. These results indicate that insulin-responsive fetal tissues (liver and skeletal muscle) adapt to the hypoglycemic-hypoinsulinemic IUGR environment with mechanisms that promote glucose utilization, particularly for glucose storage, including increased insulin action, glucose production, shunting of glucose utilization to glycogen production, and maintenance of glucose transporter concentrations.     

In utero substrate restriction by placental insufficiency or maternal undernutrition decreases optical redox ratio in foetal perirenal fat

Intrauterine growth restriction (IUGR) can result from reduced delivery of substrates, including oxygen and glucose, during pregnancy and may be caused by either placental insufficiency or maternal undernutrition. As a consequence of IUGR, there is altered programming of adipose tissue and this can be associated with metabolic diseases later in life. We have utilised two sheep models of IUGR, placental restriction and late gestation undernutrition, to determine the metabolic effects of growth restriction on foetal perirenal adipose tissue (PAT). Two-photon microscopy was employed to obtain an optical redox ratio, which gives an indication of cell metabolism. PAT of IUGR foetuses exhibited higher metabolic activity, altered lipid droplet morphology, upregulation of cytochrome c oxidase subunit genes and decreased expression of genes involved in growth and differentiation. Our results indicate that there are adaptations in PAT of IUGR foetuses that might be protective and ensure survival in response to an IUGR insult.     

Interaction of human placental ribonuclease with placental ribonuclease inhibitor

The interactions of human placental ribonuclease inhibitor (PRI) with bovine pancreatic ribonuclease (RNase) A and human angiogenin, a plasma protein that induces blood vessel formation, have been characterized in detail in earlier studies. However, studies on the interaction of PRI with the RNase(s) indigenous to placenta have not been performed previously, nor have any placental RNases been identified. In the present work, the major human placental RNase (PR) was purified to homogeneity by a five-step procedure and was obtained in a yield of 110 micrograms/kg of tissue. The placental content of angiogenin was also examined and was found to be at least 10-fold lower than that of PR. On the basis of its amino acid composition, amino-terminal sequence, and catalytic properties, PR appears to be identical with an RNase previously isolated from eosinophils (eosinophil-derived neurotoxin), liver, and urine. The apparent second-order rate constant of association for the PR.PRI complex, measured by examining the competition between PR and angiogenin for PRI, is 1.9 X 10(8) M-1 s-1. The rate constant for dissociation of the complex, determined by HPLC measurement of the rate of release of PR from its complex with PRI in the presence of a scavenger for free PRI, is 1.8 X 10(-7) s-1. Thus the Ki value for the PR.PRI complex is 9 X 10(-16) M, similar to that obtained with angiogenin, and 40-fold lower than that measured with RNase A. Complex formation causes a small red shift in the protein fluorescence emission spectrum, with no significant change in overall intensity. The fluorescence quantum yield of PR and the Stern-Volmer constant for fluorescence quenching by acrylamide are both high, possibly due to the presence of an unusual posttranslationally modified tryptophan residue at position 7 in the primary sequence.     

High prevalence of hypertension and placental insufficiency, but no in utero HIV transmission, among women on HAART with stillbirths in Botswana

Background

Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth.

Methods

HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed.

Results

Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART).

Conclusions

In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.     

Evolution of placental proteases

The placenta is a critical organ in mammals required for the transport of nutrients from the mother to the fetus during gestation. Other critical functions of the placenta include hormone regulation and immune regulation. The origin of the mammals and early placenta is relatively recent in evolutionary terms, and consequently there are few placenta-specific genes. In two separate branches of mammalian evolution, gene duplications have given rise to two large families of protease genes that are expressed only by placental tissues. A family of aspartic protease genes is expressed only in artiodactyls, and a family of cysteine protease genes is expressed only in rodents. These genes have probably evolved to perform specific functions in the placenta that are carried out by broader specificity proteases in mammalian species that do not express these proteases.     

Nontrophoblastic placental tumors

The aim of the study was to investigate potential influence of placental tumors on fetal outcome. The study comprised 10 cases of placental tumors. The analysis included the sonographic assessment of the tumor, signs of fetal anemia, as well as signs of hemodynamic disturbances or heart failure, and intrauterine treatment. The fetal hemodynamic was examined on the basis of Doppler blood flow in the umbilical artery and vein, middle cerebral artery, and ductus venous. The evaluation of fetal heart included the measurement of heart size, blood flow through cardiac valves and the assessment of fetal heart function based on cardiovascular score. The fetal outcome was also assessed according to birthweight, gestational age at delivery, pH, Ap score at 5th minute, abnormal neurological development and the need of intrauterine therapy. Ten cases of placental tumors were prenatally detected from 1999 to 2011. Among them 7 cases of hypoechogenic, non-vascularized cysts were identified and these neither effected the hemodynamics nor complicated fetal outcome. The vascularized tumors (chorioangioma) were the cause of severe anemia and hemodynamic disturbances and these led to fetal cardiac heart failure. In all cases of vascularized tumors from 2-3 intrauterine transfusion were performed. Rich vascularized tumors (chorioangioma) may cause hemodynamic disturbances and fetal heart failure. This may require intrauterine treatment and may result in abnormal fetal outcome and neurological development.     

Control of placental protein production by retinoic acid in cultured placental cells

Summary The synthesis of human chorionic gonadotropin (HCG), the subunit of HCG (HCGα), and pregnancy-specific β₁-glycoprotein (PSβG) was studied in temperature senstive (ts), simian virus 40 (SV40)tsA mutant-transformed human first trimenster placental (SPA255-26) cells. Retinoic acid increased the production of HCG and PSβG but inhibited the production of HCGα in these cells. Passage ofSPA255-26 placental cells in medium containing retinoic acid induced a stable altered phenotype characterized by elevated levels of HCG and PSβG and a reduced level of HCGα. The retinoic acid induced phenotypic changes in these placental cells were reversible; removal of retinoic acid immediately decreased the production of HCG and PSβG while increasing the production of HCGα. The ratio of HCG to HCGα in controlSPA255-26 cells was approximately 0.1; this ratio in creased to 4.8 in cells maintained in medium containing retinoic acid. Similarly, the HCG-to-HCGα ratio increased in choriocarcinoma cells maintained in retinoic acid containing medium. Our data suggest that retinoic acid may be needed to maintain a blanced production of HCG, HCGα, and PSβG in placental cells in vitro. Retinoic acid may also play a role in modulating placental protein production during pregnancy.     

Restriction of placental growth in sheep enhances placental metabolism of fetal beta-endorphin-like immunoreactivity

The opioid polypeptide beta-endorphin is present in fetal blood but it is not clear whether its source is the fetus or the placenta. We therefore measured beta-endorphin in extracts of fetal femoral arterial and umbilical venous blood plasma in sheep by radioimmunoassay to determine whether the fetus or the placenta is the major source of beta-endorphin in the fetal circulation. Chromatographic analysis of extracts of fetal arterial plasma showed that beta-lipotropin and other precursors of beta-endorphin made only a minor contribution to the immunoreactivity detected. Concentrations of immunoreactive beta-endorphin were higher in the femoral artery than in the umbilical vein in fetal sheep between 113 and 128 days of pregnancy. Therefore the placenta removes beta-endorphin or a closely related polypeptide of fetal origin from the umbilical circulation in sheep at this stage of gestation. Acute hypoxaemia and hypoglycaemia increase the concentrations of immunoassayable beta-endorphin in blood plasma of adult and fetal sheep, but little is known about the effects of chronic hypoxaemia or hypoglycaemia on the circulating levels of beta-endorphin and related polypeptides in the fetus. Therefore we also measured immunoreactive beta-endorphin in blood plasma from fetal sheep in which growth retardation in association with restricted placental growth was produced by removal of endometrial caruncles before mating. Intra-uterine growth retardation was accompanied by chronic hypoglycaemia and chronic hypoxaemia in the fetuses. This was not associated with higher concentrations of beta-endorphin-like immunoreactivity in fetal arterial or umbilical venous plasma, but was accompanied by significantly increased placental extraction of fetal immunoreactive beta-endorphin from the umbilical circulation.(ABSTRACT TRUNCATED AT 250 WORDS)