Placental Oxygen Consumption Research Articles

An MRI approach to assess placental function in healthy humans and sheep.

Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental by MRI was ∼4mlmin-1 kg-1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential. It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( ) and in healthy humans and sheep. Women (n=20) and Merino sheep (n=10; 23sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36±2weeks and 128±9days, respectively; mean±SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal and . Maternal (mlmin-1 kg-1 fetus) to the gravid uterus was similar in humans and sheep (human=54±15, sheep=53±21, P=0.854), while fetal (human=25±4, sheep=22 ± 5, P=0.049) was slightly lower in sheep. Uteroplacental and fetal (mlmin-1 kg-1 fetus; uteroplacental: human=4.1±1.5, sheep=3.5±1.9, P=0.281; fetus: human=6.8±1.3, sheep=7.2±1.7, P=0.426) were similar between species. Late gestational uteroplacental:fetal ratio did not change with age (human, P=0.256; sheep, P=0.121). Human umbilical blood flow (mlmin-1 kg-1 fetus) decreased with advancing age (P=0.008), while fetal was preserved through an increase in oxygen extraction (P=0.046). By contrast, sheep fetal was preserved through stable umbilical flow (mlmin-1 kg-1 ; P=0.443) and oxygen extraction (P=0.582). MRI derived measurements of uteroplacental and fetal between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'.

NO placental inflammation.

NO placental inflammation.

Placental Gas Exchange and the Oxygen Supply to the Fetus.

The oxygen supply of the fetus depends on the blood oxygen content and flow rate in the uterine and umbilical arteries and the diffusing capacity of the placenta. Oxygen consumption by the placenta is a significant factor and a potential limitation on availability to the fetus. The relevance of these several factors as well as responses to acute or sustained hypoxia has been explored in the sheep model. In addition, much has been learned in the context of hypobaric hypoxia by studying human populations that have resided at high altitude for varying periods of time. Embryonic development occurs under anaerobic conditions and even the fetus is adapted to a low oxygen environment. Nevertheless, there is a reserve capacity, and during acute hypoxia the fetus can counter a 50% reduction in oxygen delivery by increasing fractional extraction. During sustained hypoxia, on the other hand, fetal growth is slowed, although oxygen consumption is unaltered when corrected for fetal mass. Similarly, birth weight is reduced in humans living at high altitude even if the effect is tempered in those with a long highland ancestry. Placental mass changes little during sustained hypoxia in sheep or humans at high altitude. This conceals the fact that there are structural changes and that placental oxygen consumption is reduced. The underlying mechanisms are a current focus of research. One intriguing possibility is that increased anaerobic metabolism of glucose in the placenta spares oxygen for the fetus but reduces its supply of substrate and thereby limits fetal growth.

Labor inhibits placental mechanistic target of rapamycin complex 1 signaling

IntroductionLabor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. MethodsPlacental tissue was collected from healthy, term pregnancies (n = 15 no-labor; n = 12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFĸB p65 and PPARγ DNA binding activity was measured in isolated nuclei. ResultsLabor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFĸB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusionSeveral placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor.

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called "placental insufficiency", originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 (NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.

Placental Oxygen Consumption. Part I: In Vivo Studies—A Review

At term of pregnancy, oxygen consumption by the human or ovine placenta accounts for 40 per cent of total oxygen uptake by the gravid uterus. In the sheep, most oxygen is used for oxidative phosphorylation of glucose; the remainder is probably utilized for non-mitochondrial processes. The ATP yield is expended mainly in protein synthesis and cation transport. The fractional protein synthesis rate of ovine placenta is 60 per cent per day. Applying these data to man, protein synthesis is estimated to account for about 30 per cent of placental oxygen uptake. Probably this reflects the high rates of synthesis of peptide and steroid hormones. The Na+gradient is the basis for secondary active transport of amino acids and other substances, and the Na+–K+-pump probably accounts for 20–30 per cent of oxygen uptake, with a smaller contribution from Ca2+-ATPase. Placental oxygen uptake remains constant during acute reductions in uterine oxygen supply and is maintained at the expense of the fetus. In the longer term, in experimental models of fetal growth restriction, placental oxygen consumption is reduced to a greater extent than fetal oxygen consumption. Placental oxygen consumption is greatly reduced under in vitro experimental conditions, due largely to an inadequate oxygen supply. This results in reduced protein synthesis and possibly inhibition of Na+–K+-ATPase. However, if the placenta is subjected to hyperoxia, by raising the Po2of the medium, there is an increase in anaerobic glycolysis and structural damage may ensue. Premature exposure of trophoblast to high oxygen tensions in vivo may result in reduced villous branching, but this is likely to be a cause, rather than a consequence, of reduced fetal growth and oxygen consumption.

Placental Oxygen Consumption. Part II: In Vitro Studies—A Review

The human placenta in vivo consumes large amounts of oxygen. After delivery the placenta is exposed to anoxia and under in vitro experimental conditions oxygen consumption is only a fraction of in vivo estimates. In spite of a reduced oxygen supply, structural and functional integrity of the tissue is surprisingly well preserved. Special metabolic adjustments in the sense of ‘partial metabolic arrest’ may be the explanation for a remarkable survival capacity of placental tissue and reduction of protein synthesis seems to be an important component of metabolic slowdown. The potential significance of this special feature of placental metabolism for the in vivo situation is discussed.

Regulation of placental metabolism by glucose supply

Glucose is supplied to the placenta and fetus from the maternal plasma according to concentration-dependent mechanisms exhibiting saturation kinetics that are mediated by facilitative transporter proteins on both the maternal-facing microvillus and fetal-facing basal trophoblast membranes. Placental glucose transport to the fetus requires a net maternal-to-fetal plasma glucose concentration gradient that is determined by placental as well as fetal glucose consumption. Fetal plasma glucose concentration, independent of maternal glucose concentration, regulates the partition of placental glucose uptake into transfer to the fetus and consumption by the placenta. Placental transport capacity increases with advancing gestation, probably by an increased number of transporter proteins as surface area increases. Placental glucose consumption contributes to most or all of placental lactate and fructose production and other less well defined non-oxidative pathways of carbon metabolism. Placental glucose consumption accounts for at least 50% of placental oxygen consumption which remains independent of short-term or long-term changes in placental glucose supply, thus requiring varying amounts of other carbon substrates. Placental glucose supply, therefore, plays a key role in regulating placental glucose metabolism and placental carbon balance, and interacts reciprocally with other carbon substrates to maintain placental oxidative metabolism.

Effect of inorganic mercury on in vitro placental nutrient transfer and oxygen consumption

The effect of mercury (HgCl 2) on placental amino acid and glucose transfer as determined by the use of their nonmetabolizable radioactive analogues, aminoisobutyric acid (AIB) and 3- o-metyhl glucose (3MG), respectively, was studied in an in vitro perfusion model of a term human placenta. Hg 2+ was found to decrease the transfer and accumulation of AIB without affecting 3MG transfer. It was also found to decrease the placental oxygen consumption rate. Placental circulation and tissue morphology remained intact, as demonstrated by the antipyrine transfer rate, and by electron microscopy, respectively. The mechanism by which Hg 2+ may interfere with placental amino acid transfer and accumulation is discussed. Although much higher concentrations than those found in the ordinary polluted environment were used, this is the first report showing that Hg 2+ interferes with an essential human placental function in a system employing a whole human placental cotyledon. This finding may indicate the possible involvement of Hg 2+ in impaired organogenesis in early pregnancy or deranged fetal growth during the last trimester.

A theoretical analysis of the effect of placental metabolism on fetal oxygenation under conditions of limited oxygen availability

The purpose of this theoretical paper is to examine the effects of placental metabolism on fetal oxygenation under conditions of limited oxygen availability. Features of the mathematical model used here include: (1) ordinary non-linear differential equations defining the oxygen partial pressure profiles in the maternal and fetal streams for a concurrent flow pattern; (2) the presence of maternal and fetal blood flow shunts; (3) consumption of oxygen by a metabolically active placenta; and (4) modification of the fetal input to the placenta by changing the rate of fetal oxygen consumption in response to changes in the rate of oxygen delivered to the fetus via the umbilical vein. Model parameters were chosen to be well within the range of values cited in the literature. Based on these calculations, we conclude that: (1) under normal conditions, approximately one-half of the fetal uterine-umbilical venous oxygen partial pressure difference can be attributed to placental oxygen consumption; (2) utilization of fetal oxygen to help maintain the metabolic activities of the placenta does not significantly impair fetal oxygenation under normal conditions; (3) consumption of oxygen by the placenta will have a significant detrimental effect on the rate of oxygen delivered to the fetus if oxygen availability is compromised; and (4) for the same rate of maternal oxygen delivered to the placenta, maternal hypoxemia has a significantly greater adverse effect on fetal oxygenation than does maternal anemia.

Metabolic and cardiovascular effects on fetal sheep of sustained reduction of uterine blood flow.

The effects on the fetus and placenta of graded reductions of uterine blood flow to 30-90% of control have been studied in sheep at days 125-143 of pregnancy. Reduction of uterine flow to 70-90% of control had little effect upon fetal oxygenation or heart rate or blood pressure but elevated fetal plasma catecholamine concentration. Reduction of flow to 30-50% of control depressed fetal arterial and umbilical venous PO2 but had little effect upon oxygen consumption unless the umbilical venous value fell below about 14 mmHg when it was depressed by up to 30%. Placental oxygen consumption did not fall and was therefore maintained at the expense of the fetus. Fetal arterial pressure rose by 10-12 mmHg and heart rate fell by about 30 beats/min during the first 10-15 min then rose above its initial value. Plasma adrenaline and noradrenaline concentrations rose progressively at a rate which increased with greater degrees of asphyxia. When uterine blood flow was reduced below one-half of normal, net placental consumption of glucose fell and there was evidence of substantial provision of glucose and lactate from the fetus. Fetal production of lactate increased sharply and much of this appeared to be consumed by the placenta at a rate sufficient to account entirely for the deficit in net glucose consumption. The results are consistent with the hypothesis that the fetus senses even small changes in uterine blood flow that are alone insufficient to elicit significant blood gas changes. When the fall in uterine flow caused by arterial compression is relatively large, nutrient supply to the placenta is maintained at the expense of the fetus and as a result of fetal glucose and lactate production. The elevation of fetal arterial PCO2 appears to enhance fetal responses to hypoxia. The results are discussed in relation to the fetal responses to brief and prolonged reductions in uterine blood flow.

241 HUMAN FETAL UMBILICAL BLOOD FLOW ESTIMATION BY APPLICATION OF THE BOHR PRINCIPLE

Fetal (F) and placental (P) oxygen consumption (VO2) were calculated using continuous indirect calorimetry in 6 awake gravidas not in labor at 38 wks gestation with 6 AGA fetuses undergoing elective cesarean section utilizing complete lumbar epidural analgesia. Maternal (M) steady state was judged by stability of minute ventilation, MVO2, and percent carbon dioxide in expired air. Readings were obtained 10 min before delivery, 5–10 min after cord clamping, and 10–20 min after placental removal. Blood samples were obtained from umbilical vein (γ) and artery (α) for oxygen content (O2). A trimmed, drained P weight was obtained within 30 min of delivery. MVO2 decreased after cord clamping (FVO2), and still further after placental removal (PVO2). Fetal umbilical blood flow (f) was calculated from the Fick equation by solving for f=FVO2/([O2]γ – [O2]α). These data agree favorably with measurements of FVO2, PVO2, and f in other mammalian species. Some of the variability in f is accounted for by one baby whose f=338 ml/min/kg, FVO2 = 13.0 ml/min/kg, and whose F/P=11.0. We speculate that babies attached to small placentas relative to their body size may have a higher metabolic rate during cesarean section than babies attached to large placentas relative to their body size.

Partition of maternal nutrients to the placenta and fetus in the sheep.

Utilizing the Fick Principle, the fluxes of oxygen and glucose leaving the uterine circulation and entering the fetal umbilical circulation were measured simultaneously in 35 chronically catheterized sheep. Additionally, the distribution of placentally produced lactate into the uterine and umbilical circulations was measured by the same techniques. Under unstressed conditions, placental oxygen consumption accounted for approximately half the oxygen exiting the uterine circulation. Placental glucose consumption averaged 75% of the glucose exiting the uterine circulation, and this proportion increased with decreasing glucose concentration in the maternal artery. Lactate was produced at a high rate by all placentae, and distributed disproportionately to the fetus, in spite of higher fetal lactate concentration. Fetal metabolism was aerobic, as demonstrated by a high rate of net oxygen consumption and a high rate of net lactate consumption. Fetal oxygen metabolism correlated well with fetal weight and with the sum of net fetal lactate and glucose consumption.

Human placental oxygen transfer and consumption. Dissociation by cooling or use of respiratory enzyme inhibitors

The regulation of oxygen placental transfer is studied during the in vitro perfusion of normal postpartum human placental lobules. Oxygen consumption of the placental tissue is measured during the perfusion of the fetal placental circulation alone (single perfusions). To evaluate the transplacental diffusion of oxygen, fetal placental and uteroplacental circulations are simultaneously perfused (dual perfusions). The results obtained at various temperatures (37 and 4 °C) and after use of respiratory enzyme inhibitors (fluorodinitrobenzene and oligomycin) prove that oxygen consumption is related to trophoblast physiological activity, while oxygen transfer relies on a simple diffusion mechanism.

Oxygen consumption and diffusion in isolated human term placental lobules perfused in vitro.

An in vitro model has been perfected to perfuse maternal and foetal circulations in the isolated lobule of term human placentae. The present paper gives the results obtained using this experimental model to investigate placental oxygen consumption and oxygen diffusion from the maternal to the foetal placental circulation.

Placental oxygen consumption in vitro: IV. Variations with Apgar score

Placental oxygen consumption was studied by Warburg respirometric techniques in 617 placentas obtained at delivery. Correlations between Apgar score, gestational age, and infant weight were analyzed. Elevated oxygen consumption was encountered among placentas from infants with low Apgar scores, short gestational age, and low birth weight when these factors were examined separately. When corrections were applied for fetal size, the correlation between placental oxygen consumption and Apgar score disappeared.

Placental oxygen consumption in vitro: V. Hypertensive disorders

Respirometric examination of placentas obtained from 71 patients with documented toxemia of pregnancy, hypertensive cardiovascular disease, and renal disorders is presented. Pre-eclampsia was found associated with progressively diminishing placental oxygen consumption with increasing severity of clinical syndrome. Placentas from patients with hypertensive cardiovascular disease, on the other hand, utilized somewhat more oxygen than expected. Pre-eclampsia superimposed on hypertensive disease resulted in normal levels of placental metabolic activity. Patients with documented renal disease, and to a lesser extent those with albuminuria, had only moderate elevations of oxygen consumption. The potential significance of these findings is discussed in light of recent studies suggesting that renin production secondary to placental ischemia may be etiologic in toxemia.

Placental oxygen consumption in vitro: III. Oxytocin effect

Placental oxygen utilization was studied by respirometric techniques to determine the effect of varying substrate concentrations of oxytocin. It was found that oxygen uptake was depressed significantly at levels of natural and synthetic oxytocin exceeding 10 mU. per milliliter, well above that usually reached in clinical usage. Vasopressin suppressed metabolic activity somewhat also. The preservative agent, chlorobutanol, was shown to act similarly, accounting for all the effect seen with vasopressin, but only part of that encountered with oxytocin. Preservative-free, high concentration, synthetic oxytocin was free of depressive effect, on the other hand. The implications are discussed.

Respiratory Function of the Placenta as Determined with Carbon Monoxide in Sheep and Dogs*

A technique is described for studying the respiratory function of the placenta using carbon monoxide, a gas whose exchange across the placenta between the maternal and fetal circulations is limited by diffusion rather than blood flow. During the steady state before the introduction of CO, the normal concentration of carboxyhemoglobin in the ewe, [COHb](M), is approximately 0.90%, and that in the fetus is 2.9%, the ratio [COHb](F)/[COHb](M) being 3.2. In dogs the corresponding values are 1.9%, 4.8%, and 2.4%. After the introduction of CO into the mother animal, CO diffused across the placenta slowly with an equilibration half-time of approximately 2 hours. The average carbon monoxide diffusing capacity (D(Pco)) of the placenta during maternal to fetal exchange was 0.54 ml per (minute x mm Hg x kg fetal weight) (SD +/- 0.13) in sheep and 0.57 ml per (minute x mm Hg x kg) (SD +/- 0.18) in dogs. The fetal to maternal placental diffusing capacity in two sheep was 0.54 ml per (minute x mm Hg x kg). Calculations considering the relative rates of reaction of O(2) and CO with red cell hemoglobin and the relative rates of diffusion of the two gases suggest that the true D(Po2) should be about 1.2 to 2 times greater than the D(Pco) or 0.65 to 1.1 per (minute x mm Hg x kg). This is about 5 times greater than the reported value of D(Po2) calculated from measurements of P(O2) in the mixed uterine and umbilical venous blood. With a diffusing capacity of this magnitude the maternal and fetal placental end capillary P(O2) would approach equilibrium, becoming too small to measure, and the calculation of D(Po2) would be unreliable. We suggest that the apparent end capillary P(o2) gradients of 15 to 20 mm Hg, obtained from sampling uterine and umbilical venous blood, result from a combination of uneven distribution of maternal and fetal placental blood flow and from placental oxygen consumption.

Placental oxygen consumption in vitro: II. Total uptake as an index of placental function

The average total oxygen consumption of a series of placentas has been determined to be 86,800 ± 2,500 μl per hour. It appears to be unrelated to changing gestational age and to placental or fetal weight after the twenty-eighth week of gestation, and remains essentially a constant during the third trimester. Corresponding clinical material has been studied and the total placental oxygen requirement has been found to be diminished in association with pre-eclampsia, fetal distress, depressed infants, and in infarcted placentas; and to be elevated after prolonged general inhalation anesthesia. The potential significance of these findings is discussed.