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L-Arginine Transport by the Microvillous Plasma Membrane of the Syncytiotrophoblast from Human Placenta in Relation to Nitric Oxide Production: Effects of Gestation, Preeclampsia, and Intrauterine Growth Restriction

Nuffield Department of Obstetrics and Gynecology (P.T.-Y.A.), John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom OX3 9DU; and Academic Unit of Child Health (D.T., S.W.D., J.D.G., C.P.S.) and School of Biological Sciences (C.P.S.), University of Manchester, St. Mary’s Hospital, Manchester, United Kingdom M13 OJH

Address all correspondence and requests for reprints to: Dr. P. Ayuk, Nuffield Department of Obstetrics and Gynecology, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU. E-mail: paul.ayuk{at}obs-gyn.ox.ac.uk

Abstract

Nitric oxide (NO) is an important regulator of placental perfusion, and its production is dependent on the activity of substrate (L-arginine) transporters. In the light of evidence for altered NO production in the feto-placental unit in preeclampsia and intrauterine growth restriction (IUGR), we investigated gestational changes in human placental L-arginine transport by systems y⁺ and y⁺L in purified microvillous plasma membrane vesicles. We also examined the effect of preeclampsia and IUGR on the activity of these transport systems and the relationship between transporter activity and NO production (nitrate/nitrite concentrations) in the feto-placental unit. Between first trimester and term, there was a significant positive correlation between system y⁺ activity and gestational age (r = 0.36; P = 0.013; n = 47), but a significant negative correlation between system y⁺L activity and gestational age (r = -0.6; P < 0.0001; n = 47). The activity of these transport systems was not altered in preeclampsia or IUGR. In placentas from normal term pregnancies, there was no correlation between the activity of microvillous plasma membrane L-arginine transporters and nitrate/nitrite concentrations in umbilical venous plasma or placental homogenate.

ADEQUATE UTERO-PLACENTAL and feto-placental blood flow are essential for normal intrauterine growth. There is substantial evidence that nitric oxide (NO) production by the feto-placental unit plays an important role in the regulation of placental bed vascular resistance (1) and that this mechanism might be deranged in complications of pregnancy such as intrauterine growth restriction (IUGR) and preeclampsia (2, 3, 4, 5). The mechanisms controlling NO production in the normal placenta are poorly understood. NO is produced from the amino acid L-arginine by NO synthases. In endothelial cells (which express the constitutive isoform of NO synthase) and inflammatory cells (which express the inducible isoform), NO synthesis has been shown to be dependent on extracellular L-arginine and its transport across the plasma membrane (6, 7). Alterations in placental L-arginine transport may therefore contribute to the reported changes in NO production by the feto-placental unit in IUGR/preeclampsia (2, 3).

NO synthases are expressed in several cell types in the human placenta, but endothelial NO synthase expression is particularly high in the syncytiotrophoblast (8). This synctiotrophoblast is also the transporting epithelium of the human placenta, with a variety of transport proteins in both its microvillous (maternal facing) and basal (fetal facing) plasma membranes. These transport systems will play a role in delivering nutrient to the fetus as well as in providing substrate for syncytiotrophoblast metabolism (9). In pregnancies complicated by IUGR, the activity of some, but not all, of these transport systems has been shown to be altered compared with that in normal pregnancies. For example, the activities of the system A transporter (transports alanine and glycine), taurine transporter, and leucine transporter in syncytiotrophoblast microvillous plasma membrane (MVM) vesicles have all been reported to be significantly reduced compared with normal (10, 11, 12). Lysine transport activity in the MVM, which will probably use the same cationic amino acid transport systems as arginine, was unaffected by IUGR (12). These data suggest that alterations in syncytiotrophoblast transport activity might be an important facet of pregnancy pathologies. However, no previous study has directly addressed arginine transport in placentas from women delivering IUGR babies or examined any transport system in placentas from preeclamptic patients without the complication of IUGR. In terms of syncytiotrophoblast NO production, arginine might be provided by transport from the maternal circulation across the MVM or from the fetal circulation across the basal membrane. Here we focus on the MVM and test the hypothesis that L-arginine transport is altered in placentas from preeclamptic patients compared with those from women with normal pregnancies. We also studied a population of women delivering IUGR babies, both for comparison to preeclampsia and to the previous study of lysine transport in this condition (12).

Cationic amino acid transport systems in MVM have been well characterized (13, 14). Our recent study (14) of first trimester and term MVM showed that L-arginine transport is mediated by two systems: a high affinity, low capacity system that was sensitive to inhibition by neutral amino acids such as L-glutamine and L-leucine (system y⁺L), and a lower affinity, higher capacity system that was insensitive to glutamine inhibition (system y⁺). This study also showed differences in activities between first trimester and term as well as in the expression of one of the proteins, 4F2hc, associated with system y⁺L activity (14). As preeclamptic patients and those with IUGR babies are likely to deliver preterm, the present investigation incorporated characterization of normal gestational changes in MVM system y⁺ and system y⁺L activities by examining placentas from first, second, and third trimester pregnancies. Finally we examined in normal pregnancy the relationship between the activity of MVM L-arginine transporters and nitrate/nitrite concentrations in the feto-placental unit.

Subjects and Methods

This study was approved by our local research ethics committee. Informed consent was obtained for the use of placentas after termination of pregnancy. To study the ontogeny of placental L-arginine transport, placentas were obtained from first (8–11 wk) and second (12–16 wk) trimester pregnancies after surgical termination of pregnancy for social reasons (Clause C of the United Kingdom Abortion Act 1967). Placentas from first trimester pregnancies were pooled to obtain more than 20 g tissue over a period of less than 3 h in ice-cold mannitol buffer (300 mM mannitol, 10 mM HEPES-Tris, and 1 mM MgSO₄, pH 7.4). Placentas were also obtained from third trimester pregnancies after spontaneous preterm labor without prolonged prelabor rupture of the fetal membranes (<24 h) or after elective preterm cesarean section for nonobstetric indications. Placentas were also collected as soon as possible after delivery (within 30 min) from normal term pregnancies, from pregnancies complicated by preeclampsia and IUGR, and from gestational age-matched controls. Preeclampsia was defined as gestational proteinuric hypertension, and patients were selected only when all of the following criteria were met: nulliparity, normotensive (blood pressure, <140/90) and nonproteinuric at the time of booking for antenatal care (< 20-wk gestation), development of hypertension (blood pressure, >140/90 on at least two occasions at least >4 h apart) at more than 20-wk gestation, iv development of proteinuria (>300 mg urinary protein excretion over 24 h or >2+ on reagent strip testing) at more than 20 wk gestation. IUGR was identified by the presence of abnormal feto-placental perfusion as determined by umbilical artery Doppler velocimetry.

MVM vesicles were prepared using the method of Mg²⁺ precipitation and differential centrifugation as described previously (10, 15). Vesicles were suspended in intravesicular buffer (50 mM KCl, 50 mM choline chloride, 100 mM mannitol, and 20 mM HEPES-Tris, pH 7.4). The protein concentration in MVM was determined by the method of Lowry et al. (16). Vesicle purity was determined by alkaline phosphatase enrichment as described previously (15). Vesicles were stored overnight at 4 C, and the uptake of [³H]arginine (0.2 µM; NEN Life Science Products) in extravesicular buffer (50 mM NaCl, 50 mM KCl, 100 mM mannitol, and 20 mM HEPES-Tris, pH 7.4) was determined using the method of rapid filtration (14). We found previously (14) that uptake via both system y⁺ and y⁺L increased linearly with time up to 60 sec. Therefore, here initial rate of [³H]arginine uptake by MVM was determined by measuring uptake at 15, 30, 45, and 60 sec and calculating the gradient of the uptake vs. time plot using linear regression (PRISM 2.01, GraphPad Software, Inc., San Diego, CA). Our previous study also showed that 10 mM L-glutamine was sufficient to completely saturate system y⁺L (14). Therefore, 10 mM L-glutamine was used to separate the transport activities of system y⁺ and y⁺L as follows: uptake in the presence of 10 mM L-glutamine = system y⁺ activity; total uptake - system y⁺ activity = system y⁺L activity.

Nitrate/nitrite concentrations were determined in placental homogenate (as a measure of placental NO production) and umbilical venous plasma (as a measure of fetal NO production) after delivery at term using the Griess reaction. Umbilical venous blood was collected from the cord insertion in Li-heparin and plasma obtained after centrifugation at 3000 rpm (Beckman Coulter, Inc., Palo Alto, CA) for 10 min. Plasma samples were snap-frozen and stored at -80 C. Placentas were then used to prepare MVM as previously described (10, 14, 15). Fifty to 100 g placental tissue were homogenized in 2.5x (wt/vol) mannitol buffer as part of the procedure for MVM preparation. Five grams of this homogenate were homogenized in 3 x (wt/vol) distilled water, aliquoted, snap-frozen in liquid nitrogen, and stored at -80 C before further analysis. The protein concentration in placental homogenate was determined by the method of Lowry et al. (16). Nitrate/nitrite concentrations in umbilical venous plasma and placental homogenate were determined using the nitrate/nitrite colorimetric assay kit (Alexis Corp., Nottingham, UK) according to the manufacturer’s instructions.

Data presentation and statistical analysis

Data are presented, when appropriate, as the mean ± SE, with n being the number of placentas studied or, for first trimester studies, the number of pooled placental preparations. The relationship between the activity of arginine transporters and gestational age was examined using Pearson’s correlation coefficient. Arginine uptake by first trimester, second trimester, and term MVM and by preeclamptic, IUGR, and control MVM were analyzed using ANOVA. The relationship between MVM arginine uptake and nitrate/nitrite concentrations in the feto-placental unit was examined using Pearson’s correlation coefficient.

Results

MVM were prepared from first trimester (10 preparations of pooled tissue), 12–41 wk gestation (n = 47, of which 27 were at term, 38–41 wk), preeclamptic (n = 10), IUGR (n = 8), and gestational age-matched control (n = 10) placentas. There was no significant difference in MVM alkaline phosphatase enrichment in first trimester (19.6 ± 1.3; n = 10), second trimester (21.8 ± 3.0; n = 8), and third trimester (17.6 ± 0.7; n = 39) placentas (P > 0.05, by ANOVA).

As shown in Table 1, the activity of system y⁺L was significantly higher in first trimester compared with term MVM (P < 0.0001) and in second trimester compared with term MVM (P < 0.001), but was not significantly different between first and second trimester MVM (P > 0.05). In contrast, system y⁺ activity was significantly lower in second trimester compared with term MVM (P < 0.05), but was not significantly different between first and second trimesters or between first trimester and term MVM (Table 1). Total MVM [³H]arginine uptake showed a significant negative correlation with gestational age (data not shown). When the activities of the two transport systems were examined separately, there was a significant negative correlation between system y⁺L activity and gestational age (12–41 wk; r = -0.6; P < 0.0001; n = 47; Fig. 1A). On the other hand, there was a significant positive correlation between system y⁺ activity and gestational age (12–41 wk; r = 0.36; P = 0.013; n = 47; Fig. 2A). Between 34–41 wk gestation, there was a significant fall in system y⁺L activity with gestational age (r = -0.59; P = 0.0001; n = 37; Fig. 1B), whereas the activity of the system y⁺ transporter remained unchanged (r = -0.067; P = 0.69; n = 37; Fig. 2B). The slope of the regression line describing the relationship between system y⁺L activity and gestational age between 34–41 wk (-0.04 ± 0.009 pmol/mg protein·min/wk) was almost 4 times the slope between 12–41 wk (-0.011 ± 0.002 pmol/mg protein·min/wk). In all placentas studied, there was a trend toward a negative association between the activities of the two transport systems (r = -0.24; P = 0.072; n = 57; data not shown).

View larger version (17K): [in this window] [in a new window]   Figure 1. Relationship between MVM system y+L activity and gestation age. MVM vesicles were prepared from first, second, and third trimester placentas, and the initial rate of [3H]arginine uptake by system y+L (glutamine sensitive) was determined by the method of rapid filtration. Data from first trimester placentas are shown for comparison only and were not used in determination of the correlation coefficient. Between 12–41 wk gestation, there was a significant negative correlation between system y+L activity and gestational age (r = -0.6; P < 0.0001; n = 47; Fig. 1A). A significant negative correlation was also observed at 34–41 wk gestation (r = -0.59; P = 0.0001; n = 37; Fig. 1B).

View larger version (18K): [in this window] [in a new window]   Figure 2. Relationship between MVM system y+ activity and gestational age. MVM vesicles were prepared from first, second, and third trimester placentas, and the initial rate of [3H]arginine uptake by system y+ (glutamine insensitive) was determined by the method of rapid filtration. Data from first trimester placentas are shown for comparison only and were not used in determination of the correlation coefficient. Between 12–41 wk gestation, there was a significant positive correlation between MVM system y+ activity and gestational age (r = 0.36; P = 0.013; n = 47; Fig. 2A). Between 34–41 wk gestation, however, there was no significant relationship between system y+ activity and gestational age (P > 0.05; Fig. 2B).

View larger version (11K): [in this window] [in a new window]   Figure 3. MVM system y+ and system y+L activity in IUGR (n = 8), preeclampsia (PE; n = 10), and gestational age-matched controls (n = 10). MVM vesicles were prepared from placentas in pregnancies complicated by IUGR, PE and in gestational age-matched controls. The initial rate of [3H]arginine uptake was determined in the presence and absence of 10 mM L-glutamine. There were no significant differences in the activity of MVM arginine transporters in the three groups. Data are the mean + SEM.

Discussion

This is the first study examining the gestational regulation of human placental cationic amino acid transport. The data are limited by the paucity of placentas from the 17- to 34-wk gestation period. This is a consequence of ethical, legal and medical limitations associated with late termination of pregnancies. The presence of infection or prolonged preterm rupture of the fetal membranes meant that many placentas from pregnancies delivered at less than 34 wk gestation could not be used for this study. Some information on the gestational regulation of MVM cationic amino acid transport, however, may be deduced from an examination of the trends at earlier and later gestation ages.

The observed gestational changes in MVM L-arginine transporter activity should be considered in the context of the kinetic properties of the transport systems and how these impact on activity measurements using radioisotope tracer studies. System y⁺L is a higher affinity, lower capacity system, whereas system y⁺ has a lower affinity, but a higher capacity (14). At low substrate concentrations (as used in these studies, 0.2 µM), the rate of uptake will be inversely proportional to the K_m. At substrate concentrations well above the K_m, however, the rate of uptake will be independent of the K_m and proportional to V_max. In the in vitro model used in this study, system y⁺L will make a disproportionately higher contribution to tracer uptake compared with its contribution to amino acid uptake in vivo. Furthermore, system y⁺L will also interact with neutral amino acids such as L-leucine and L-glutamine in vivo. The kinetic characteristics of these transport systems therefore indicate that system y⁺ activity will be the predominant MVM cationic amino acid transport activity in vivo. We therefore conclude that under physiological conditions MVM cationic amino acid transport increases between 12–41 wk gestation, and the critical period of change is from 12–34 wk. This increase in addition to structural adaptations in the placenta (17) should increase cationic amino acid supply to the fetus. The physiological significance of the marked gestational age-related fall in system y⁺L activity remains to be determined. System y⁺L is an amino acid exchanger (18) and mediates the exchange of cationic amino acids for neutral amino acids plus Na⁺. The direction of this exchange activity in placental MVM has not been determined. The gestation age-related fall in system y⁺L activity may therefore have an impact on the supply of cationic or neutral amino acids. There is also evidence for the intracellular compartmentalization of L-arginine metabolism (7, 19), and thus the possibility exists that systems y⁺ and y⁺L may supply different compartments within the syncytiotrophoblast.

The activity of L-arginine transport systems in MVM has been examined in IUGR, preeclampsia, and gestational age-matched controls. Pregnancies complicated by preeclampsia were identified using a widely used definition of the syndrome. IUGR was defined by abnormalities of feto-placental perfusion, as assessed by umbilical artery Dopplers with no restriction on birth weight for gestational age. At term, birth weight for gestation age has been demonstrated to be a poor predictor of perinatal outcome (20). In addition, differences of up to 823 g have been observed in the gestational age-specific cut-off values used by various investigators to define abnormal intrauterine growth (21). Some of these differences may be related to maternal ethnic background. Our sample was drawn from a multiethnic population, and it was therefore inappropriate to apply an intrauterine growth normogram derived from a population of which the sample studied was not representative. This notwithstanding, the birth weight of IUGR fetuses was significantly lower than that of fetuses from pregnancies complicated by preeclampsia or controls, with no significant difference in gestational age at delivery.

In contrast to the activity of the system A transporter (10), taurine transport (11), and leucine transport (12), there was no significant difference in the activity of MVM L-arginine transport systems y⁺ and y⁺L in IUGR. These data are in agreement with a recent report that L-lysine uptake by MVM was not altered in IUGR (12). These data suggest that altered NO production (nitrate/nitrite concentration) by the feto-placental unit in IUGR (2) is not associated with an alteration in MVM L-arginine uptake. In addition, our data add to the growing body of evidence that defects in placental MVM amino acid transport associated with IUGR are specific to certain transport systems only. The activity of MVM cationic amino acid transport systems was also unaltered in preeclampsia. In this study birth weight was not significantly different in preeclampsia compared with controls. With respect to nutrient supply for fetal growth, therefore, it was not surprising that no significant difference was observed in the activity of cationic amino acid transport systems in MVM. With respect to L-arginine supply for NO synthesis, these data suggest that increased NO production (nitrate/nitrite concentration) by the feto-placental unit in preeclampsia (3) is not associated with increased MVM L-arginine uptake. There is no net loss of nitrate/nitrite across the umbilical circulation (22). We therefore used nitrate/nitrite concentrations in placental homogenate as a measure of placental NO production.

In placentas at term, we did not observe any association between the activity of MVM L-arginine transporters and nitrate/nitrite concentrations in umbilical venous plasma or placental homogenate, consistent with the lack of effect of IUGR or preeclampsia on these transporters. We cannot, however, conclude that the gestational age-related change in the activity of the system y⁺ and y⁺L transporters in MVM are unassociated with changes in NO production, as the changes in transporter activity occurred before term. In the light of these data, a full examination of the relationship between the activity of MVM L-arginine transporters and NO production would require a detailed study of placentas in the 12- to 37-wk period. The syncytiotrophoblast also serves the vital function of transferring amino acids from the maternal to the fetal compartment. The amino acid concentrations within the syncytium will therefore depend on the rate of uptake by MVM and the rate of exit via the basal plasma membrane. An examination of L-arginine transport by placental basal plasma membrane vesicles in normal and complicated pregnancy is therefore essential.

In summary, this study has characterized significant gestation age-related changes in L-arginine transporter activity in the MVM of the syncytiotrophoblast in normal pregnancy. Neither IUGR nor preeclampsia affects this transporter activity. Future studies need to address whether L-arginine transport in the basal membrane of the syncytiotrophoblast is affected by gestation or pregnancy pathology.

Footnotes

This work was supported by the British Heart Foundation.

Abbreviations: IUGR, Intrauterine growth restriction; NO, nitric oxide; MVM, microvillous plasma membrane.

Received June 11, 2001.

Accepted October 17, 2001.

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