Subcutaneous maternal resveratrol treatment increases uterine artery blood flow in the pregnant ewe and increases fetal but not cardiac growth.

KEY POINTS: Substrate restriction during critical developmental windows of gestation programmes offspring for a predisposition towards cardiovascular disease in adult life. This study aimed to determine the effect of maternal resveratrol (RSV) treatment in an animal model in which chronic fetal catheterisation is possible and the timing of organ maturation reflects that of the human. Maternal RSV treatment increased uterine artery blood flow, fetal oxygenation and fetal weight. RSV was not detectable in the fetal circulation, indicating that it may not cross the sheep placenta. This study highlights RSV as a possible intervention to restore fetal substrate supply in pregnancies affected by placental insufficiency. ABSTRACT: Suboptimal in utero environments with reduced substrate supply during critical developmental windows of gestation predispose offspring to non-communicable diseases such as cardiovascular disease (CVD). Improving fetal substrate supply in these pregnancies may ameliorate the predisposition these offspring have toward adult-onset CVD. This study aimed to determine the effect of maternal resveratrol (RSV) supplementation on uterine artery blood flow and the direct effects of RSV on the fetal heart in a chronically catheterised sheep model of human pregnancy. Maternal RSV treatment significantly increased uterine artery blood flow as measured by phase contrast magnetic resonance imaging, mean gestational fetal PaO2 and SaO2 as well as fetal weight. RSV was not detectable in the fetal circulation, and mRNA and protein expression of the histone/protein deacetylase SIRT1 did not differ between treatment groups. No effect of maternal RSV supplementation on AKT/mTOR or CAMKII signalling in the fetal left ventricle was observed. Maternal RSV supplementation is capable of increasing fetal oxygenation and growth in an animal model in which cardiac development parallels that of the human.

Broccoli sprout supplementation during pregnancy prevents brain injury in the newborn rat following placental insufficiency.

Chronic placental insufficiency and subsequent intrauterine growth restriction (IUGR) increase the risk of hypoxic-ischemic encephalopathy in the newborn by 40 fold. The latter, in turn, increases the risk of cerebral palsy and developmental disabilities. This study seeks to determine the effectiveness of broccoli sprouts (BrSp), a rich source of the isothiocyanate sulforaphane, as a neuroprotectant in a rat model of chronic placental insufficiency and IUGR. Placental insufficiency and IUGR was induced by bilateral uterine artery ligation (BUAL) on day E20 of gestation. Dams were fed standard chow or chow supplemented with 200mg of dried BrSp from E15 - postnatal day 14 (PD14). Controls received Sham surgery and the same dietary regime. Pups underwent neurologic reflex testing and open field testing, following which they were euthanized and their brains frozen for neuropathologic assessment. Compared to Sham, IUGR pups were delayed in attaining early reflexes and performed worse in the open field, both of which were significantly improved by maternal supplementation of BrSp (p<0.05). Neuropathology revealed diminished white matter, ventricular dilation, astrogliosis and reduction in hippocampal neurons in IUGR animals compared to Sham, whereas broccoli sprout supplementation improved outcome in all histological assessments (p<0.05). Maternal dietary supplementation with BrSp prevented the detrimental neurocognitive and neuropathologic effects of chronic intrauterine ischemia. These findings suggest a novel approach for prevention of cerebral palsy and/or developmental disabilities associated with placental insufficiency.

Resposta clínica e metabólica de potros neonatos em relação aos achados histopatológicos da placenta na égua / Clinical and metabolic response of neonatal foals related to histopathology finds in mare placenta

Avaliaram-se as respostas clínica e metabólica de potros neonatos em relação aos achados histopatológicos da placenta na égua. Foram avaliados dois grupos de éguas da raça Puro Sangue Inglês - um grupo-problema (n=25) e um grupo-controle (n=25), de acordo com os achados da placenta. O exame dos potros constou de avaliação clínica geral, hematologia e bioquímica sérica. O exame histopatológico da placenta apresentou resultado compatível com a apresentação clínica do potro, sendo que a presença de lesões inflamatórias resultou na produção de potros debilitados. A presença de lesões degenerativas não comprometeu o estado clínico do neonato, mas pode ser responsável pela manifestação de distúrbios subclínicos, evidenciados pelo aumento das taxas de AST e GGT. A ureia pareceu ser um indicador de dano renal decorrente de insuficiência placentária em potros neonatos.

The placenta represents the major communication between the mare and the fetus during the gestational period, and this suggests that any disturbance in the placenta can be an indicator of gestational damage with risk to the fetus. The aim of this paper was to evaluate the clinical and metabolic responses of the newborn foals related with the findings from the histopathological examination of the placenta. This study was conducted in a farm located in Bagé-RS, Brazil, where were evaluated two groups of Throughbred mares for this case-control study: One Problem Group (N=25) and the Control Group (n=25), based on the placental findings. The foal's evaluation was based on general clinical examination, hematology and serum biochemistry. Results from the placenta histopathological exams were compatible with clinical presentation of the foals, with the presence of inflammatory lesions resulting in the production of debilitated foals. The presence of degenerative lesions in the placenta does not compromise the clinical features of the newborn, but they can be responsible for the manifestation of sub-clinical disturbances, evidenced by increased levels of AST and GGT. Urea seems to be an indicator of renal damage due to placental insufficiency in neonatal foals.

[Peculiarities of metabolic rearrangement of gas-transporting function of the blood in the pregnant women under the influence of medical ozone applied in obstetrical practice].

This clinical and laboratory study was designed to evaluate the influence of an ozone-oxygen mixture on the characteristics of blood oxygen supply in pregnant women presenting with chronic placental insufficiency. The study has demonstrate that dosed ozone application modulates the oxygen-transporting function of the blood and promotes adaptive capacities of the organism by activation of aerobic metabolism and stabilization of cellular membranes. It is concluded that the proposed method can be recommended for the treatment of women with the complicated course of pregnancy in order to improve their endurance of and resistibility to the action of hypoxemia.

Placental restriction of fetal growth decreases IGF1 and leptin mRNA expression in the perirenal adipose tissue of late gestation fetal sheep.

Placental restriction (PR) of fetal growth results in a low birth weight and an increased visceral fat mass in postnatal life. We investigated whether PR alters expression of genes that regulate adipogenesis [IGF1, IGF1 receptor (IGF1R), IGF2, IGF2R, proliferator-activated receptor-gamma, retinoid-X-receptor-alpha], adipocyte metabolism (lipoprotein lipase, G3PDH, GAPDH) and adipokine signaling (leptin, adiponectin) in visceral adipose tissue before birth. PR was induced by removal of the majority of endometrial caruncles in nonpregnant ewes before mating. Fetal blood samples were collected from 116 days gestation, and perirenal visceral adipose tissue (PAT) was collected from PR and control fetuses at 145 days. PAT gene expression was measured by quantitative RT-PCR. PR fetuses had a lower weight (PR 2.90 +/- 0.32 kg; control, 5.12 +/- 0.24 kg; P < 0.0001), mean gestational arterial Po(2) (P < 0.0001), plasma glucose (P < 0.01), and insulin concentrations (P < 0.02), than controls. The expression of IGF1 mRNA in PAT was lower in the PR fetuses (PR, 0.332 +/- 0.063; control, 0.741 +/- 0.083; P < 0.01). Leptin mRNA expression in PAT was also lower in PR fetuses (PR, 0.077 +/- 0.009; control, 0.115 +/- 0.013; P < 0.05), although there was no difference in the expression of other adipokine or adipogenic genes in PAT between PR and control fetuses. Thus, restriction of placental and hence, fetal substrate supply results in decreased IGF1 and leptin expression in fetal visceral adipose tissue, which may alter the functional development of the perirenal fat depot and contribute to altered leptin signaling in the growth-restricted newborn and the subsequent emergence of an increased visceral adiposity.

Lung maturation in small for gestational age fetuses from pregnancies complicated by placental insufficiency or maternal hypertension.

BACKGROUND: Clinical studies suggest that respiratory outcome of infants born preterm may be influenced by placental insufficiency and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. If so, one could expect to see differences in lung maturation indices (lecithin/sphingomyelin (L/S) ratio and lamellar body count (LBC)) in the amniotic fluid. The present study investigates lung maturation indices of preterm small for gestational age (SGA) fetuses with or without abnormal Doppler ultrasound examination and with or without maternal hypertension/HELLP syndrome. STUDY DESIGN: Retrospective cohort study of 76 neonates born in our center between 1997 and 2003 with gestational age (GA) <34 weeks, birth weight

Maternal taurine supplementation in the late pregnant rat stimulates postnatal growth and induces obesity and insulin resistance in adult offspring.

An adequate supply of taurine during fetal life is important for normal beta-cell development and insulin action. An altered availability of taurine may programme glucose metabolism in utero and result in type 2 diabetes in adult age. We examined whether maternal taurine supplementation in late pregnant rats affects postnatal growth, adult body composition, insulin sensitivity and endogenous insulin secretion in intrauterine growth restricted (IUGR) and normal offspring. Uterine artery ligation or sham operations were performed on gestational day (GD) 19. Taurine supplementation was given to half of the dams from GD 18 until term, resulting in four groups of offspring: sham (n = 22), sham/taurine (n = 22), IUGR (n = 22) and IUGR/taurine (n = 24). The offspring were studied at 12 weeks of age. In offspring with normal birth weight, fetal taurine supplementation markedly stimulated postnatal growth. In sham/taurine females, fat depots, plasma free fatty acid and leptin concentrations were increased, and insulin sensitivity was reduced. Insulin sensitivity was unaltered in IUGR and IUGR/taurine offspring. However, whereas IUGR offspring showed little catch-up growth, 50% of IUGR/taurine animals displayed complete catch-up at 12 weeks of age, and these animals had increased fat depots and reduced insulin sensitivity. In conclusion, taurine supplementation in late gestation resulted in accelerated postnatal growth, which was associated with adult obesity and insulin resistance in both IUGR and normal offspring. This effect was particularly evident in females. These data suggest that fetal taurine availability is an important determinant for postnatal growth, insulin sensitivity and fat accumulation.

Ephedrine and phenylephrine for the treatment of maternal hypotension in a chronic sheep model of increased placental vascular resistance.

BACKGROUND: We hypothesized that ephedrine and phenylephrine are equal with respect to uterine and placental haemodynamics and fetal acid-base status after exposure to maternal hypoxaemia and hypotension in a chronic sheep model of increased placental vascular resistance (R(UA)). METHODS: At 114-135 days gestation, chronically instrumented fetal sheep underwent placental embolization leading to increased R(UA). Twenty-four hours after embolization, the ewes were anaesthetized and randomized to receive boluses of ephedrine (n=7) or phenylephrine (n=6) for epidural-induced hypotension after maternal hypoxaemia. Uterine (Q(UtA)) and placental (Q(UA)) volume blood flows and uterine vascular resistance (R(UtA)) and R(UA) were recorded. Uterine (PI(UtA)) and umbilical artery (PI(UA)) pulsatility indices were obtained by Doppler ultrasonography. Fetal arterial blood samples were analysed for acid-base values and lactate concentrations. RESULTS: During hypotension, Q(UtA), fetal pH, BE, and Po(2) decreased whereas R(UtA), PI(UtA), R(UA), and fetal lactate concentration increased. With ephedrine, Q(UtA), R(UtA), PI(UtA), R(UA), and fetal Po(2) returned to baseline. Fetal pH, BE, and lactate concentration did not change from hypotensive values. With phenylephrine, Q(UtA) remained lower (P=0.007) and R(UtA) (P=0.007), PI(UtA) (P=0.013), and R(UA) (P=0.050) higher than at baseline. Fetal Po(2) returned to baseline and fetal pH and BE did not change from hypotensive values. However, fetal lactate concentration increased further (mean difference 1.49, 95% confidence interval 0.72-2.26 mmol litre(-1); P=0.004). CONCLUSIONS: In a chronic sheep model of increased placental vascular resistance, compared with ephedrine administration, phenylephrine administration was associated with impaired uterine and placental haemodynamics and increased fetal lactate concentrations.

[Early severe restriction of intrauterine growth: a therapeutic alternative]. / Restricción del crecimiento intrauterino grave de inicio temprano: una alternativa terapéutica.

It is presented the case of the second pregnancy of a 36 year-old patient with antecedent of preeclampsia that was solved, at full-term, with a Caesarean operation by means of which was obtained a healthy new born. The patient began her prenatal control at 29th week. Ultrasound made at her admittance showed a fetus with an approximated weight of 451 grams. The patient was hospitalized until completing protocol of study for restriction of severe fetal growth. At 34.5 weeks, an ultrasonographical control showed an alteration in venous duct; for that reason it was decided to interrupt pregnancy abdominally. There were no surgical complications and was obtained a phenotypically normal new born, male, weight of 820 grams and size of 33 cm, who was referred to the Instituto Nacional de Perinatologia. At 43.3 weeks he was discharged from hospital with a weight of 1,840 grams. At the present he's fed with fortified milk.

Effects of intrauterine food restriction and long-term dietary supplementation with L-arginine on age-related changes in renal function and structure of rats.

We have previously demonstrated that restricting intrauterine food by 50% in 3-mo-old rats produced lower nephron numbers and early-onset hypertension, the latter being normalized by L-arginine administration. In 18-mo-old rats, such restriction increased glomerulosclerosis. In this study, we expanded our investigation, evaluating functional, morphologic, and immunohistochemical parameters in intrauterine-food-restricted 18-mo-old rats, either receiving L-arginine (RA18) or not (R18). Age-matched, non-food-restricted controls were assigned to similar groups with L-arginine (CA18) and without (C18). After weaning, L-arginine was given daily for 17 mo. No functional or morphologic changes were observed in C18 rats. The R18 rats developed early-onset hypertension, which persisted throughout the observation period, as well as significant proteinuria from 12 mo on. In RA18 rats, L-arginine decreased both blood pressure levels and proteinuria, and glomerular diameter was significantly smaller than in R18 rats (115.63 +/- 2.2 versus 134.8 +/- 1.0 mum, p < 0.05). However, in RA18 rats, glomerular filtration rate remained depressed. Although L-arginine prevented glomerulosclerosis (R18 = 14%, RA18 = 4%; p < 0.05), glomerular expression of fibronectin and desmin was still greater in RA18 rats than in controls. Our data show that, although L-arginine prevented hypertension and proteinuria, glomerular injury still occurred, suggesting that intrauterine food restriction may be one of the leading causes of impaired renal function in adult life.

Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency.

Severe uteroplacental insufficiency causes cerebral apoptosis in the fetus. Moderate uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and increases the risk of postnatal neurological morbidity. In the rat, uteroplacental insufficiency and IUGR affect cerebral gene expression of Bcl-2 and predispose the newborn IUGR rat toward cerebral apoptosis when challenged with perinatal hypoxia. Expression of Bcl-2, as well as the proapoptotic protein Bax, is regulated by p53. p53 also induces MDM2 transcription, which functions to limit further p53-induced apoptosis. The predisposition of the IUGR fetus toward cerebral apoptosis suggests that the p53-MDM2 "functional" circuit may be perturbed in the newborn IUGR rat brain. We hypothesized that MDM2 cerebral expression does not increase in response to increased p53 expression or increased levels of phospho-p53 (Ser15), an activated form of p53. To prove this hypothesis, we induced IUGR through bilateral uterine ligation of the pregnant rat. Uteroplacental insufficiency significantly increased p53 mRNA, total p53 protein, and phospho-p53 (Ser15) protein levels in the brain at term. Increased expression of phospho-p53 (Ser15) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were localized to the CA1 region of the hippocampus, the subcortical and periventricular white matter, and the amygdala of the IUGR rat brain. In contrast, uteroplacental insufficiency decreased cerebral MDM2 mRNA and phospho-MDM2 (Ser166) protein levels in the IUGR rat pups. We conclude that the cerebral MDM2 response to increased p53 expression is not present in the newborn IUGR rat pup, and we speculate that this contributes to the predisposition of the IUGR fetus toward perinatal and long-term neurodevelopmental morbidities.

L-Arginine effects on blood pressure and renal function of intrauterine restricted rats.

We have previously demonstrated that 3-month-old rats submitted to 50% intrauterine food restriction showed a decreased number of nephrons with increased glomerular diameter, a fact that suggests compensatory hypertrophy. In the present study, we extended the investigation and performed serial blood pressure measurements and renal function evaluation in 8- and 12-week-old rats submitted to 50% intrauterine food restriction (groups R8 and R12) and in age-matched control rats (groups C8 and C12). After weaning, six to eight animals from each group received oral supplements of 2% L-arginine ( L-arg) solution for 4 or 8 weeks (groups CA8, CA12, RA8, RA12). Our findings showed that mean blood pressure (MBP), which was significantly increased from 8 weeks on in R rats, markedly decreased after L-arg supplementation. In control animals, no alterations in MBP were observed with L-arg. Proteinuria was within normal limits in all groups studied but L-arg caused a significant decrease in this parameter in both the RA8 and RA12 groups. Glomerular filtration rate (GFR, ml/min per kg) was significantly decreased in the C8 control group (3.75+/-0.12) and in both restricted groups R8 and R12, (2.47+/-0.13 and 3.76+/-0.16, respectively) compared with the C12 group (6.09+/-0.31; P<0.05 for all comparisons). L-Arg caused an increase in GFR only in the younger groups, C8 and R8. In a separate set of experiments, acetylcholine (ACh)-induced relaxation was examined in mesenteric arteries. The R12 group showed a significant impairment of the response to ACh, which returned to normal values after L-arg supplementation. Urinary excretion of NO(x) (NO3- + NO2-) was significantly decreased in 8- and 12-week-old food-restricted rats relative to control rats. Our data indicate that, besides the known decrease in absolute nephron number, disturbances in the production/sensitivity to the L-arg-nitric oxide system may contribute to the early appearance of hypertension in the offspring of mothers submitted to significant food restriction.

Alterations of placental vascular function in asthmatic pregnancies.

Asthma during pregnancy is associated with low-birthweight neonates at term but the mechanisms that cause this outcome are presently unknown. Changes in placental vascular function resulting from asthma or its treatment could contribute to altered fetal growth. We have prospectively followed women with asthma and a control group of women without asthma during their pregnancies, classified them based on asthma severity and glucocorticoid intake, and monitored fetal development and placental blood flow using Doppler ultrasound at 18 and 30 wk gestation. The placentae from these women were collected after delivery and vascular responses to dilator and constrictor agonists assessed using an in vitro placental perfusion method. At 18 wk gestation, umbilical artery flow velocity waveforms were significantly reduced in the moderate and severe asthmatic groups and in those women using high-dose inhaled glucocorticoid for the treatment of their asthma (ANOVA, p < 0.05). However, at 30 wk gestation there were no significant differences in umbilical artery flow velocity between control and asthmatic women (ANOVA, p > 0.05). Corticotropin-releasing hormone (CRH), a potent vasodilator that acts via the nitric oxide pathway, caused a dose-dependent vasodilatory response in all placentae in vitro. However, CRH-induced dilation was significantly reduced in moderate and severe asthmatics (ANOVA, p < 0.05). Vasoconstrictor responses to potassium chloride and prostaglandin F(2alpha) were reduced in placentae from moderate and severe asthmatic women (ANOVA, p < 0.05). These studies demonstrate significant differences in placental vascular function in pregnancies complicated by asthma, which may relate directly to the asthma or be a consequence of the associated glucocorticoid treatment. These changes in vascular function in asthmatic pregnancies may contribute to the low-birthweight outcome observed in this condition.

[Heparin electrophoresis by sinusoidal modulated currents in the combined treatment of chronic fetoplacental insufficiency]. / Geparin-élektroforez sinusoidal'nymi modulirovannymi tokami v kompleksnom lechenii khronicheskoi fetoplatsentarnoi nedostatochnosti.

Physicochemical grounds are presented for application of heparin electrophoresis with sinusoidal modulated currents (SMC) for correction of impaired fetouteroplacental circulation and blood rheocoagulation basing on the evidence obtained in 95 gravidae on gestation trimester II. 25% of them were in the group of risk by chronic fetoplacental insufficiency (CFPI), 63% had compensated CFPI and 12% of patients--subcompensated CFPI. 50 patients were treated with drugs SMC heparin electrophoresis, 25 patients received SMC and basic medication, 20 patients were given drugs only. Compared to drugs or SMC treatment only, SMC heparin electrophoresis produced more beneficial effects on hemostasis, barrier placental function, reduced frequency of premature and operative labour.