Metabolism of glucose by fetus and placenta of sheep. The effects of normal fluctuations in uterine blood flow

The metabolism by the fetus and placenta of [2-3H, U-14C]glucose infused into fetal sheep has been studied. Uptake of glucose from the fetus by the placenta and transfer to the ewe, as well as placental metabolism of glucose to fructose and lactate have been quantified. About two-thirds of the glucose removed from the fetal circulation was taken up by placenta. Less than 15% of this passed back into the maternal circulation, the remainder was converted, at roughly equivalent rates, into lactate and fructose, most of which was transferred back to the fetus. It seems likely that little of this glucose is oxidised by the placenta. This data indicates that there are substrate cycles between the placenta and fetus, one possible function of which is to limit fetal glucose loss back to the mother; lactate and fructose have limited placental permeability. At uterine blood flow rates in the middle of the normal range net glucose uptake by the placenta from the maternal circulation was about 7-fold higher than that from the fetus. About 20% of this was transported to the fetus, 50% was oxidised and much of the remainder converted to lactate and transferred back to the ewe. Labelling patterns in fructose and lactate make it unlikely that this placental pool of glucose mixes freely with that derived from uptake from the fetus. Net movement of glucose across the placenta is markedly influenced by fluctuations in uterine blood flow over the normal range of 500-3000 ml/min. At low flow rates there is net output of glucose from the fetus to the placenta, and in some instances from the placenta to the ewe, i.e. there is evidence of net utero-placental production of glucose to the ewe separate from output by the fetus. There is a close linear relationship between uterine glucose supply (maternal arterial concentration x uterine blood flow) and net balance across the placenta. As uterine supply of glucose falls there is increased uptake by the placenta of glucose from the fetal circulation and corresponding enhanced recycling of fructose and lactate to the fetus. This production of fructose and lactate by the placenta may function to reduce glucose loss from the fetus to the ewe. Hence at high rates of placental uptake of glucose from the fetus placental production of lactate and particularly fructose may approach saturation and allow significant backflow of glucose from the fetus to the ewe. Under these conditions glucose uptake may in part sustain placental oxygen consumption.     

Regional blood flow distribution in fetal sheep with intrauterine growth retardation produced by decreased umbilical placental perfusion

To determine the capacity of the fetus to adapt to chronic O2 deficiency produced by decreased placental perfusion in the early development of growth retardation, we embolized the umbilical placental vascular bed of fetal sheep for a period of 9 days. Fetal umbilical placental embolization decreased arterial O2 content by 39%, decreased total placental blood flow by 33%, and produced a 20% reduction in mean fetal body weight. Neither the combined ventricular output nor the regional blood flow distribution was significantly different between the 8 growth-retarded and 7 normally grown fetuses despite the 39% decrease in fetal arterial O2 content. Thus a 33% reduction in total placental blood flow restricts normal fetal growth, but does not exceed the placental circulatory reserve capacity necessary to maintain normal basal metabolic oxygenation. Because the proportion of combined ventricular output to the placenta at rest is decreased in late IUGR fetuses but not in early IUGR fetuses, despite chronic oxygen deficiency, we conclude that the growth retarded fetus maintains a normal regional blood flow distribution until the placental circulatory reserve capacity is depleted.     

The effect of elevation of maternal plasma catecholamines on the fetus and placenta of the pregnant sheep

To study the effects of reduced uterine blood flow on fetal and placental metabolism, adrenaline has been infused at physiological doses (0.5 microgram/min per kg) into the circulation of the pregnant sheep. This gives a reduction of about one third of uterine blood flow at days 120-143 of pregnancy, but causes no significant change in umbilical blood flow. In contrast to the effects of constricting the uterine artery to reduce blood flow to a similar degree, placental oxygen consumption was reduced and that, together with a large increase in lactate production, indicated the placenta became hypoxic. The fetal blood gas status and hence oxygen consumption was not affected significantly. A consistent arterio-venous difference for glucose across the umbilical or uterine circulations was not detected unless the uterine blood flow was comparatively high. Glucose balance across the uterus showed a close linear relationship with uterine blood flow and more particularly with the supply of glucose to the uterus. There was clear evidence for glucose uptake by the placenta and fetus and also glucose output by both. The latter was more common when uterine blood flow was comparatively low or reduced by adrenaline infusion. The results are consistent with the concept that glucose supply has to be maintained to the placenta even at the expense of fetal stores, although lactate can substitute if there is enhanced output because of fetal hypoxia. They indicate that placental mobilisation of glycogen can lead to a net output of glucose to the mother. The manner of communicating to the fetus changes in placental state that occur during maternal adrenaline infusion is not clear. However towards the end of the 60 min infusion, elevation of fetal plasma adrenaline, probably resulting from a breakdown of the placental permeability barrier, may be an important signal.     

Placental transfer of glucose

The rates of glucose transfer from maternal blood to pregnant uterus and from placenta to fetus were measured in eight sheep at spontaneously occurring glucose concentrations (control state) and while the fetus, the mother, or both were receiving a constant infusion of glucose. In addition two fetuses received insulin infusions. In the control state the net glucose flux from placenta to fetus was only 27 +/- 2.6% (SEM) of the net flux from the uterine circulation to the pregnant uterus. An empirical equation describing the relationship between placental glucose transfer and arterial plasma glucose concentrations was derived from the data and compared with equations constructed on the basis of methematical models of placental function. This analysis indicates that: (1) placental glucose transfer is mediated by carriers with Km approximately equal to 70 mg/dl; (2) the rate of glucose transfer from mother to fetus is limited primarily by the transport characteristics and glucose consumption rate of the placenta; (3) under normal conditions of placental perfusion, glucose transfer is approximately 15% less than it would be if placental blood flows were infinitely large.     

Exercise responses in pregnant sheep: blood gases, temperatures, and fetal cardiovascular system

In an effort to examine the effects of maternal exercise on the fetus we measured maternal and fetal temperatures and blood gases and calculated uterine O2 consumption in response to three different treadmill exercise regimens in 12 chronically catheterized near-term sheep. We also measured fetal catecholamine concentrations, heart rate, blood pressure, cardiac output, blood flow distribution, blood volume, and placental diffusing capacity. Maternal and fetal temperatures increased a mean maximum of 1.5 +/- 0.5 (SE) and 1.3 +/- 0.1 degrees C, respectively. We corrected maternal and fetal blood gas values for the temperatures in vivo. Maternal arterial partial pressure of O2 (PO2), near exhaustion during prolonged (40 min) exercise at 70% maximal O2 consumption, increased 13% to a maximum of 116.7 +/- 4.0 Torr, whereas partial pressure of CO2 (PCO2) decreased by 28% to 27.6 +/- 2.2 Torr. Fetal arterial PO2 decreased 11% to a minimum of 23.2 +/- 1.6 Torr, O2 content by 26% to 4.3 +/- 0.6 ml X dl -1, PCO2 by 8% to 49.6 +/- 3.2 Torr, but pH did not change significantly. Recovery was virtually complete within 20 min. During exercise total uterine O2 consumption was maintained despite the reduction in uterine blood flow because of hemoconcentration and increased O2 extraction. The decrease of 3 Torr in fetal arterial PO2 and 1.5 ml X dl -1 in O2 content did not result in major cardiovascular changes or catecholamine release. These findings suggest that maternal exercise does not represent a major stressful or hypoxic event to the fetus.     

Blood circulation and oxygen transport in the fetal guinea pig

Anaesthetized fetal guinea pigs near term were studied under conditions, where maternal placental flow of haemoglobin was maintained within the normal range. The rate of maternal fetal equilibration of intravenously injected 3H2O was found to be similar as in unanaesthetized animals (half time 4 min) indicating that fetal circulation was undisturbed under the present experimental conditions. Umbilical blood flow as determined by a modified 3H2O method was 0.13 ml . min-1 . g-1 of fetal body mass. Radioactive microspheres, injected into the fetal saphenous (jugular) vein, were distributed to the placenta, the lower body, the upper body and the lungs at a ratio of 31(47):27(39):30(6):12(8). From these data, cardiac output was calculated (0.38 ml . min-1 . g-1) and found to be almost equally distributed between the placenta, the lower body and the upper body. There was preferential streaming of the inferior vena caval blood to the upper body. There was no evidence for flow through a ductus venosus. The O2-saturation in the fetal carotid arterial blood was 59 +/- 4%. The O2-supply to the fetal tissues was estimated to be 3 times the oxygen consumption.     

On the function of placental corticotropin-releasing hormone: a role in maternal-fetal conflicts over blood glucose concentrations

Throughout the second and third trimesters, the human placenta (and the placenta in other anthropoid primates) produces substantial quantities of corticotropin-releasing hormone (placental CRH), most of which is secreted into the maternal bloodstream. During pregnancy, CRH concentrations rise over 1000-fold. The advantages that led selection to favour placental CRH production and secretion are not yet fully understood. Placental CRH stimulates the production of maternal adrenocorticotropin hormone (ACTH) and cortisol, leading to substantial increases in maternal serum cortisol levels during the third trimester. These effects are puzzling in light of widespread theory that cortisol has harmful effects on the fetus. The maternal hypothalamic-pituitary-adrenal (HPA) axis becomes less sensitive to cortisol during pregnancy, purportedly to protect the fetus from cortisol exposure. Researchers, then, have often looked for beneficial effects of placental CRH that involve receptors outside the HPA system, such as the uterine myometrium (e.g. the placental clock hypothesis). An alternative view is proposed here: the beneficial effect of placental CRH to the fetus lies in the fact that it does stimulate the production of cortisol, which, in turn, leads to greater concentrations of glucose in the maternal bloodstream available for fetal consumption. In this view, maternal HPA insensitivity to placental CRH likely reflects counter-adaptation, as the optimal rate of cortisol production for the fetus exceeds that for the mother. Evidence pertaining to this proposal is reviewed.     

Uterine blood flow, oxygen and glucose uptakes at mid-gestation in the sheep

In early ovine fetal development, the placenta grows more rapidly than the fetus so that at mid-gestation the aggregate weight of placental cotyledons exceeds fetal weight. The purpose of this study was to compare two separate methods of measuring uterine blood flow and glucose and oxygen uptakes in seven mid-gestation ewes, each carrying a single fetus. Uterine blood flow to both uterine horns was measured by microsphere and by tritiated water steady-state diffusion methodology. Calculations of tritiated water blood flows and oxygen and glucose uptakes were based on measurements of arteriovenous concentration differences across each uterine horn. The distribution of blood flow and oxygen uptake between the two uterine horns was strongly correlated with placental mass distribution. The two methods gave comparable results for uterine blood flow (457 +/- 35 vs 476 +/- 35 ml/min), oxygen uptake (457 +/- 35 vs 476 +/- 35 mumol/min), and glucose uptake (63 +/- 8 vs 64 +/- 6 mumol/min). Uterine blood flow was approximately 38% of the late gestation value and 56.1 +/- 1 times higher than umbilical blood flow. Uteroplacental oxygen consumption was about 58% of late gestation measurements and 3.9 +/- 0.5 times higher than fetal oxygen uptake. We confirm that the large placental mass of mid-gestation is associated with high levels of maternal placental blood flow and placental oxidative metabolism.     

Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

Background

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.

Methods

Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.

Principal Findings

The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.

Conclusion/Significance

Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia.     

Regulation of maternal and fetal hemodynamics by heme oxygenase in mice

Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5-15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy.     

Growth and metabolism of the placenta after unilateral fetectomy in twin pregnant ewes.

Twin-pregnant ewes underwent unilateral fetectomy (Fetx) at 50 days of gestation and were studied at 136 days. Aspects of conceptus growth and placental cellularity and metabolism in vitro were compared to those of unoperated control groups of twin-pregnant or single-pregnant ewes. Mean fetal weight in Fetx ewes tended to be greater than that of twin-pregnant ewes and was similar to that of single-pregnant ewes. Mean placental wet and dry weights were intermediate between those for naturally single- and twin-pregnant animals. Fetectomy caused a significant increase in placental protein:DNA ratio but an unchanged DNA concentration, apparently due to cellular hypertrophy in the placenta of the remaining fetus. Weight-specific rate of oxygen consumption (VO2) of fetal placental tissue in twin-pregnant ewes was higher than in Fetx or singles while maternal placental VO2 in twins tended to be lower than in either of the other two groups. These results highlight the plasticity of placental metabolism and growth, perhaps in response to altered trophic signals from the fetus. Unilateral fetectomy should prove useful in studies designed to identify these signals.     

Temperature responses following ventilation of the fetal sheep in utero

The mammalian fetus produces significant quantities of heat. This passes to the mother principally through the placenta and to a lesser extent via a pathway comprising the skin, amniotic fluid, and uterine wall. To assess the importance of the lesser pathway, temperature responses were recorded in 7 near-term fetal sheep after intrauterine ventilation with oxygen, after snaring the umbilical cord to block the placental route, and following fetal death. Four distinguishing characteristics of responses were observed: fetal temperature rose 0.10 +/- 0.03 (SEM) degrees C after oxygenation; it rose progressively an additional 0.9 +/- 0.1 degrees C during the 90-min interval after cord snaring; amniotic fluid temperature rose slowly until it was about midway between fetal and maternal temperature; and after fetal death, fetal amniotic fluid temperatures fell slowly. In a simple mathematical model with constant parameters these results could not be explained fully. It was necessary to assume that heat production rose with increased oxygenation and elevated body temperature and that ventilation increased heat transfer through the amniotic fluid, as would occur if chest wall movement were stirring the fluid. Using the model, the value for heat conductance from fetal skin to amniotic fluid was estimated to be 10.5 watts degrees C-1 under basal conditions.     

The effect of zinc levels in fetal circulation on zinc clearance across the in situ perfused guinea pig placenta

Although zinc is essential for normal fetal growth and development, little is known about factors that influence its transfer across the placenta. The in situ perfused guinea pig placenta model was used to study the influence of the zinc concentration of fetal circulation on maternofetal placental zinc transfer. A placenta of the anaesthetized sow was perfused (on the fetal side) with a physiological perfusate via the umbilical vessels, with the fetus excluded. The sow was infused intravenously with 65zinc as a tracer of placental Zn clearance, and with antipyrine as an indirect indicator of maternal placental blood flow. Maternal plasma and placental effluent samples collected at intervals were counted for 65zinc by gamma counter, and the absorbance of nitrosated antipyrine was measured at 350 nm. Varying the mean zinc concentration in the perfusate from 0.176 to 1.87 mg/L had no effect on relative zinc clearance calculated as zinc clearance/antipyrine clearance (mean +/- SEM; 0.085 +/- 0.010 vs. 0.114 +/- 0.018; n = 6; p greater than 0.05). The results suggest that short-term changes in fetal zinc status do not influence placental zinc transfer.     

Gestational protein restriction induces alterations in placental morphology and mitochondrial function in rats during late pregnancy

The placenta acts a regulator of nutrient composition and supply from mother to fetus and is the source of hormonal signals that affect maternal and fetal metabolism. Thus, appropriate development of the placenta is crucial for normal fetal development. We investigated the effect of gestational protein restriction (GPR) on placental morphology and mitochondrial function on day 19 of gestation. Pregnant dams were divided into two groups: normal (NP 17 % casein) or low-protein diet (LP 6 % casein). The placentas were processed for biochemical, histomorphometric and ultrastructural analysis. The integrity of rat placental mitochondria (RPM) isolated by conventional differential centrifugation was measured by oxygen uptake (Clark-type electrode). LP animals presented an increase in adipose tissue and triacylglycerol and a decrease in serum insulin levels. No alterations were observed in body, liver, fetus, or placenta weight. There was also no change in serum glucose, total protein, or lipid content. Gestational protein restriction had tissue-specific respiratory effects, with the observation of a small change in liver respiration (~13 %) and considerable respiratory inhibition in placenta samples (~37 %). The higher oxygen uptake by RPM in the LP groups suggests uncoupling between respiration and oxidative phosphorylation. In addition, ultrastructural analysis of junctional zone giant cells from LP placenta showed a disorganized cytoplasm, with loss of integrity of most organelles and intense vacuolization. The present results led us to hypothesize that GPR alters placental structure and morphology, induces sensitivity to insulin, mitochondrial abnormalities and suggests premature aging of the placenta. Further studies are needed to test this hypothesis.     

The effect of vasopressin on fetal oxygenation in sheep

To examine the effects of vasopressin on fetal oxygenation the hormone was infused intravenously for 1 h (1.4-3.5 mU X min-1 X kg fetal weight-1) to chronically catheterized fetal lambs in utero (113-137 days gestation). Arterial pressure rose (48.3 to 59.6 mmHg) (1 mmHg = 133.322 Pa) and heart rate fell (185.3 to 141.0 beats/min) during the infusion. There was a significant increase in fetal arterial PO2 (20.0 to 23.1 mmHg) and significant declines in pH (7.414 to 7.381) and base excess. Umbilical blood flow rose, and the percentage increase in flow (23%) was identical to the proportional rise in arterial pressure. Accompanying the rise in umbilical blood flow was a rise in umbilical oxygen delivery. But as there was no change in fetal oxygen consumption, fractional oxygen extraction by the fetus fell significantly (0.31 to 0.25). These data indicate that the vasopressin-induced rise in fetal vascular PO2 results from an increase in umbilical oxygen delivery and concomitant fall in fractional extraction. Fetal vasopressin levels are greatly elevated during hypoxia, and under conditions of reduced oxygen supply, the effects of the hormone on umbilical oxygen delivery and vascular PO2 could have definite survival value.     

Placental efficiency and intrauterine resource allocation strategies in the common marmoset pregnancy

Mothers and fetuses are expected to be in some degree of conflict over the allocation of maternal resources to fetal growth in the intrauterine environment. Variation in placental structure and function may be one way a fetus can communicate need and quality to its mother, potentially manipulating maternal investment in its favor. Whereas common marmosets typically produce twin litters, they regularly give birth to triplet litters in captivity. The addition of another fetus is a potential drain on maternal resource availability and thus a source of elevated conflict over resource allocation. Marmoset littermates share a single placental mass, so that differences in the ratio of fetal to placental weight across litter categories suggest the presence of differential intrauterine strategies of resource allocation. The fetal/placental weight ratio was calculated for 26 marmoset pregnancies, representing both twin and triplet litters, to test the hypothesis that triplet fetuses respond to intrauterine conflict by soliciting placental overgrowth as a means of accessing maternal resources. In fact, relative to fetal mass, the triplet marmoset placenta is significantly undergrown, with individual triplets associated with less placental mass than their twin counterparts, suggesting that the triplet placenta is relatively more efficient in its support of fetal growth. There still may be an important role for maternal-fetal conflict in the programming of placental structure and function. Placental adaptations that solicit potential increases of maternal investment may occur at the microscopic or metabolic level, and thus may not be reflected in the size of the placenta as a whole.     

Sexually dimorphic effects of maternal asthma during pregnancy on placental glucocorticoid metabolism and fetal growth

Human pregnancy is associated with sexually dimorphic differences in mortality and morbidity of the fetus with the male fetus experiencing the poorest outcome following complications such as pre-eclampsia, pre-term delivery and infection. The physiological mechanisms that confer these differences have not been well characterised in the human. Work conducted on the effect of maternal asthma during pregnancy, combining data collected from the mother, placenta and fetus has found some significant sex-related mechanistic differences associated with fetal growth in both normal pregnancies and pregnancies complicated by asthma. Specifically, sexually dimorphic differences have been found in placental glucocorticoid metabolism in male and female fetuses of normal pregnancies. In response to the presence of maternal asthma, only the female fetus alters placental glucocorticoid metabolism resulting in decreased growth. The male fetus does not alter placental function or growth in response to maternal asthma. As a result of the alterations in glucocorticoid metabolism in the female, downstream changes occur in pathways regulated by glucocorticoids. These data suggest that the female fetus adjusts placental function and reduces growth to compensate for maternal disease. However, the male fetus continues to grow in response to maternal asthma with no changes in placental function. This response by the male fetus may partially contribute to the increased risk of morbidity and mortality in this sex.     

Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia

IntroductionPreeclampsia is a maternal hypertensive disorder with uncertain etiology and a leading cause of maternal and fetal mortality worldwide, causing nearly 40% of premature births delivered before 35 weeks of gestation. The first stage of preeclampsia is characterized by reduction of utero-placental blood flow which is reflected in high blood pressure and proteinuria during the second half of pregnancy. In human placenta androgens derived from the maternal and fetal adrenal glands are converted into estrogens by the enzymatic action of placental aromatase. This implies that alterations in placental steroidogenesis and, subsequently, in the functionality or bioavailability of placental aromatase may be mechanistically involved in the pathophysiology of PE.MethodsSerum samples were collected at 32–36 weeks of gestation and placenta biopsies were collected at time of delivery from PE patients (n = 16) and pregnant controls (n = 32). The effect of oxygen tension on placental cells was assessed by incubation JEG–3 cells under 1% and 8% O₂ for different time periods, Timed-mated, pregnant New Zealand white rabbits (n = 6) were used to establish an in vivo model of placental ischemia (achieved by ligature of uteroplacental vessels). Aromatase content and estrogens and androgens concentrations were measured.ResultsThe protein and mRNA content of placental aromatase significantly diminished in placentae obtained from preeclamptic patients compared to controls. Similarly, the circulating concentrations of 17-β-estradiol/testosterone and estrone/androstenedione were reduced in preeclamptic patients vs. controls. These data are consistent with a concomitant decrease in aromatase activity. Aromatase content was reduced in response to low oxygen tension in the choriocarcinoma JEG–3 cell line and in rabbit placentae in response to partial ligation of uterine spiral arteries, suggesting that reduced placental aromatase activity in preeclamptic patients may be associated with chronic placental ischemia and hypoxia later in gestation.ConclusionsPlacental aromatase expression and functionality are diminished in pregnancies complicated by preeclampsia in comparison with healthy pregnant controls.     

Time-dependent physiological regulation of ovine placental GLUT-3 glucose transporter protein

We immunolocalized the GLUT-3 glucose transporter isoform versus GLUT-1 in the late-gestation epitheliochorial ovine placenta, and we examined the effect of chronic maternal hyperglycemia and hypoglycemia on placental GLUT-3 concentrations. GLUT-3 was limited to the apical surface of the trophoectoderm, whereas GLUT-1 was on the basolateral and apical surfaces of this cell layer and in the epithelial cells lining the placental uterine glands. GLUT-3 concentrations declined at 17-20 days of chronic hyperglycemia (P < 0.05), associated with increased uterine and uteroplacental net glucose uptake rate, but a normal fetal glucose uptake rate was observed. Chronic hypoglycemia did not change GLUT-3 concentrations, although uterine, uteroplacental, and fetal net glucose uptake rates were decreased. Thus maternal hyperglycemia causes a time-dependent decline in the entire placental glucose transporter pool (GLUT-1 and GLUT-3). In contrast, maternal hypoglycemia decreases GLUT-1 but not GLUT-3, resulting in a relatively increased GLUT-3 contribution to the placental glucose transporter pool, which could maintain glucose delivery to the placenta relative to the fetus when maternal glucose is low.     

Experimental models of maternal–fetal interface and their potential use for nanotechnology applications

During pregnancy, the placenta regulates the transfer of oxygen, nutrients, and residual products between the maternal and fetal bloodstreams and is a key determinant of fetal exposure to xenobiotics from the mother. To study the disposition of substances through the placenta, various experimental models are used, especially the perfused placenta, placental villi explants, and cell lineage models. In this context, nanotechnology, an area of study that is on the rise, enables the creation of particles on nanometric scales capable of releasing drugs aimed at specific tissues. An important reason for furthering the studies on transplacental transfer is to explore the potential of nanoparticles (NPs), in new delivery strategies for drugs that are specifically aimed at the mother, the placenta, or the fetus and that involve less toxicity. Due to the fact that the placental barrier is essential for the interaction between the maternal and fetal organisms as well as the possibility of NPs being used in the treatment of various pathologies, the aim of this review is to present the main experimental models used in studying the maternal–fetal interaction and the action of NPs in the placental environment.