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Perinatal Center, Departments of Physiology and Pharmacology (N.J., T.L.P., T.J.) and Anatomy and Cell Biology (B.R.J.), Göteborg University, 405 30 Göteborg, Sweden; and Academic Unit of Child Health (S.L.G.), University of Manchester, Manchester M13 0JH, United Kingdom
Address all correspondence and requests for reprints to: Nina Jansson, Perinatal Center, Department of Physiology and Pharmacology, Göteborg University, P.O. Box 432, 405 30 Göteborg, Sweden. E-mail: nina.jansson{at}fysiologi.gu.se.
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Abstract |
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Introduction |
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System A is a ubiquitously expressed amino acid transporter that mediates Na+-dependent uptake of neutral amino acids such as alanine, glycine, and glutamine (7). The transporter was recently cloned and characterized at the molecular level (8, 9). In the human syncytiotrophoblast, system A is highly polarized to the microvillous (maternal-facing) plasma membrane (10, 11), compatible with the model that neutral amino acids are highly concentrated in the syncytiotrophoblast cell by uphill transport across MVM mediated by system A (12). Subsequently, neutral amino acids are transported down their concentration gradient across the fetal-facing basal (plasma) membrane (BM) of the syncytiotrophoblast. In nonplacental tissue, system A has been shown to be regulated by a number of hormones (e.g. insulin and cortisol) and nutrition (7, 13, 14, 15). In view of the potential impact of changes in placental system A activity on fetal growth, information concerning the regulation of this transporter may provide an increased understanding for the mechanisms underlying the development of pregnancy complications associated with altered fetal growth. However, which factors regulate system A activity in the human placenta remain to be fully established. In one of the few studies available, Karl et al. (16) reported that system A activity was stimulated by insulin, dexamethasone, and glucagon in cultured human trophoblast cells.
The placenta produces a large number of hormones that are secreted into the fetal or maternal circulation or both. The primary function of some of these hormones is to adapt maternal metabolism to the specific metabolic requirements of pregnancy. In many cases, receptors for hormones produced by the placenta are present in the placenta itself, usually on the syncytiotrophoblast, compatible with an autocrine/paracrine action. This raises the possibility that the placenta regulates its own functions in response to, for example, nutrition. Leptin and placental GH are two important examples of hormones that are produced by the syncytiotrophoblast of the human placenta (17, 18). Both leptin and GH receptors have been identified on the surface of the syncytiotrophoblast cell (19, 20, 21); however, their physiological function is not well established. Maternal plasma levels of placental GH are lower in IUGR (22), and IUGR fetuses have lower leptin levels than normally grown fetuses (23).
In this study, we investigated the hormonal regulation of the syncytiotrophoblast system A amino acid transporter. We specifically chose to study hormones known to be altered in pregnancy complications associated with abnormal fetal growth and/or have been shown to alter system A activity in other tissues. To this effect, we established a technique to measure system A activity in single primary villous fragments of human placenta after 1 h incubation with leptin, GH, cortisol, epidermal GF (EGF), or insulin.
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Materials and Methods |
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All chemicals were purchased from Sigma (St. Louis, MO), except for 14C-MeAIB, which was obtained from NEN Life Science Products (Boston, MA), and GH (Genotropin), which was purchased from KABI (Uppsala, Sweden).
Buffers
DMEM containing 5.6 mM glucose, amino acids, vitamins, and minerals was used. Tyrode’s buffer was made up, containing 135 mM NaCl, 5 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2, 10 mM HEPES, and 5.6 mM glucose. In Tyrode’s medium not containing sodium, 135 mM choline chloride replaced NaCl. Because DMEM contains high amino acid concentrations, DMEM/Tyrode’s medium (mixed 1:3) was used for homone incubations (see below) to achieve a more physiological concentration of amino acids. The final concentrations of amino acids were: arginine (100 µM), cysteine (100 µM), glutamine (1000 µM), glycine (100 µM), histidine (50 µM), isoleucine (200 µM), leucine (200 µM), lysine (200 µM), methionine (50 µM), phenylalanine (100 µM), serine (100 µM), threonine (200 µM), tryptophan (20 µM), tyrosine (100 µM), and valine (90 µM). All buffers were adjusted to pH 7.4 at room temperature or 37 C, as appropriate.
Tissue
Collection of placental tissue was carried out with informed consent, according to a protocol approved by the Göteborg University Committee for Research Ethics. Placentas were obtained from full-term, uncomplicated pregnancies after either vaginal or cesarean delivery. Within 10 min after delivery, trophoblast tissue was dissected into small (approximately 5-mm3) pieces and kept at room temperature. Tissue fragments were washed in physiological saline and placed in DMEM/Tyrode’s medium (1:3). Subsequently, tissue was transported to the laboratory (transport time, 30 min) and placed in fresh DMEM/Tyrode’s medium.
Hormone production and lactate dehydrogenase (LDH) release by placental villous fragments
Villous fragment secretion of 17ß-estradiol and human placental lactogen (hPL) and the release of LDH into the incubation medium were analyzed. Villous fragments were incubated in separate vials containing 4 ml DMEM/Tyrode’s medium (1:3), at 37 C, for a total time of 3 h. After 1 and 2 h, respectively, fragments were moved to new vials containing fresh medium, allowing for measurements of hormone production and LDH-release for each 1-h period. The incubation medium was concentrated (by freeze drying) and resuspended in 0.5 ml. 17ß-Estradiol concentration was determined using an immunoassay kit (Calbiochem, La Jolla, CA) with a detection range of 13–935 pg/ml. An ELISA kit (IBL, Hamburg, Germany) with minimal detection concentration at 0.3 mg/liter was used to measure hPL. LDH release was determined using a colorimetric method (Sigma). To obtain a positive control, LDH was also measured in incubation buffers after subjecting villous fragments to sonication.
Tissue for electron microscopy
With regard to fragment size, incubation, temperature, and buffers, primary villous fragments used for electron microscopy were processed identically to fragments used for system A activity measurements. Fragments were fixed after 1, 2, or 3 h of incubation.
Scanning-electron microscopy (SEM)
Tissue was fixed overnight in a mixture of 2% paraformaldehyde and 2.5% glutaraldehyde in 0.05 M Na cacodylate (pH 7.2; 18 ml + 2 ml DMEM/Tyrode’s medium). Subsequently, osmication was carried out according to the OTOTO protocol, i.e. repeated treatments with 1% osmium tetroxide in cacodylate and a saturated solution of thiocarbohydrazide (24). Specimens were dehydrated in a series of alcohol, followed by immersion in hexamethyldisilazane, which was allowed to evaporate in a fumehood (25). The dried placental fragments were transferred to SEM stubs covered with conductive adhesive tape and were examined, without thin film metal coating, in a high-resolution 982 Gemini SEM (LEO, Oberkochen, Germany) equipped with a field emission electron source (Schottky gun) and an in-lens secondary electron detector. This instrument is fully digitized, and images were recorded as 512 x 512 or 1024 x 1024 pixel TIFF files.
Transmission-electron microscopy (TEM)
Fragments of placental tissue were fixed overnight by immersion in a mixture of 2% paraformaldehyde and 2.5% glutaraldehyde in 0.05 M Na cacodylate buffer (pH 7.2). Postfixation was performed with 1% OsO4 and 1% potassium ferrocyanide in 0.1 M cacodylate for 2 h at 4 C, followed by en bloc staining with 1% uranyl acetate in H2O for 1 h. Specimens were then dehydrated in a graded series of ethanol and infiltrated with epoxy resin (Agar 100, Agar Scientific Ltd., Stanstead, UK), followed by curing by heat. Ultrathin sections were cut in a Reichert ultramicrotome equipped with a diamond knife. They were collected on copper grids and counterstained with lead citrate and uranyl acetate before examination in a Zeiss 902 CEM. Images were recorded on photographic film and transferred to digitized image files with an Imacon Flextight high-resolution scanner (Imacon A/S, Copenhagen, Denmark).
Measurement of system A activity
Tissue was further dissected, and individual villous fragments (1-mm3) were tied to one end of a silk suture; the other end was attached to specially designed hooks made of a core of steel with a superficial layer of plastic. Fragments were placed in DMEM/Tyrode’s medium (1:3). Using this experimental setup, a number of individual fragments could be processed simultaneously through a series of incubation and washing buffers. Initially, villous fragments were incubated in DMEM/Tyrode’s medium, with or without the hormones under study, for 60 min. Incubations were carried out in 4 ml buffer at 37 C. Subsequently MeAIB uptake experiments were carried out in Tyrode’s medium only, allowing easy replacement of sodium, to obtain an Na+-free incubation buffer. Two triplicate sets of fragments were studied in parallel, one set incubated in Na+ containing Tyrode’s, the other set in Tyrode’s medium in which Na+ had been replaced with choline (representing Na+-independent uptake and nonspecific binding). After hormone incubation, fragments were washed for 2 min in Tyrode’s medium (+Na+/-Na+), followed by incubation in Tyrode’s medium (+Na+/-Na+) containing 14C-MeAIB (10.1 nmol/ml; 5.1 µCi/ml) for 20 min. Uptake was stopped by transfer of fragments into ice-cold Tyrode’s medium (+Na+/-Na+); and, after two times 15-sec agitation, fragments were placed in distilled water overnight. The next morning, fragments were removed and placed in 0.3 M NaOH overnight. Scintillation fluid was added to the vials containing distilled water, mixed thoroughly, and counted. After denaturation in NaOH, protein concentration was determined using Bradford assay (26) adapted for low protein concentrations. Subsequently, total protein of individual fragments could be calculated. Using 14C-MeAIB standards, uptakes were calculated as picomoles per milligram of protein. System A activity was determined by subtracting the uptake in Na+-free medium from the uptake in Na+-containing incubation buffers.
Effectors
The effect of insulin, GH, leptin, EGF, and cortisol on system A activity was studied. Insulin stock buffer (0.1% BSA, 1.6% glycerol) was freshly made for every experiment and mixed with insulin (bovine) to give the final concentration of 300 ng/ml. Leptin was diluted in 15 mM HCl and 7.5 mM NaOH and stored as stock solution (final concentration, 500 ng/ml) at -20 C. EGF was made up in stock buffer (10 mM H2SO4, 0.1% BSA) and was aliquoted (final concentration, 600 ng/ml) and stored at -20 C. The water soluble form of cortisol (hydrocortisone-cyklodextrine-complex) was used, freshly made for every experiment, in Tyrode’s medium (340 ng/ml). GH was diluted with distilled water, and aliquots of GH (final concentration, 500 ng/ml) were stored at +4 C for not longer than 2 wk.
Concentration series
Concentration dependence of the insulin and leptin effects on system A activity was studied. Insulin was made up as described above and diluted to the following concentrations: 600, 300, 60, 6, and 0.6 ng/ml. The leptin concentration series included the following concentrations: 500, 100, 50, 10, and 1 ng/ml.
Data presentation and statistics
Each group (n) represents experiments from one placenta, performed in triplicate Results are given as mean ± SEM. Differences between groups were evaluated statistically using ANOVA, followed by Dunnett test. A P value less than 0.05 was considered significant.
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Results |
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There was a higher production and/or release of both hPL and 17ß-estradiol in the first hour of incubation, compared with the second and third incubation hours (Fig. 1
, A and B; n = 4). LDH release from primary villous fragments was not detectable. To verify that the inability to detect LDH was not caused by technical problems associated with the assay, an increasing number of fragments were sonicated. LDH was readily detected after sonication of a single fragment, and LDH concentrations in the incubation medium increased linearly with the number of fragments sonicated (data not shown).
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A brush border of tightly packed, slender, and uniform microvilli on the surface of the syncytium was well preserved on specimens fixed at 0 h (Fig. 2A). Not all microvilli were completely erect and free; some microvilli were aggregated in small clusters. This is probably an effect of the drying procedure. Points of obvious disruption of the epithelial coat were rare. Large areas of brush border of the same appearance were recorded also after 2 and 3 h incubation (Fig. 2B), but some regions with an increased tendency of microvilli to stick to each other and to incline or flatten toward the cell surface were observed. In addition, in some fields of view, the microvilli were blunter and shorter, with a dilated tip (not shown). Still, the overall integrity of the syncytial surface was preserved.
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Examination of transversely sectioned tertiary villi did not reveal any obvious time-dependent alterations of subcellular morphology of the syncytium. The frequency and intracellular distribution of organelles were similar at different time points (Fig. 2
, C and D), with the possible exception that the apical plasma membrane, with its decoration of microvilli, could be more undulating at 3 h (Fig. 2D).
System A activity
Uptake of MeAIB into villous fragments in the presence of Na+ was linear, up to at least 30 min; at 20 min, 58% of total uptake was Na+-dependent, corresponding to transport by system A (Fig. 3). In subsequent experiments, the 20-min time point was used for measurement of system A activity.
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). Similarly, leptin (500 ng/ml) increased Na+-dependent MeAIB uptake by 37% (P < 0.05). However, neither EGF (600 ng/ml), cortisol (340 ng/ml), nor GH (500 ng/ml) altered system A activity significantly (Fig. 4, n = 14). Hormone incubation did not affect the Na+-independent uptake (data not shown).
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). There were 47%, 55%, and 52% (P < 0.05) increases of Na+-dependent MeAIB uptake in response to 0.6, 6, and 300 ng/ml insulin, respectively (n = 10). System A activity increased in a concentration-dependent fashion in response to leptin (Fig. 6). Leptin increased system A activity significantly at the two highest concentrations (100 and 500 ng/ml, n = 10), by 33% and 25%, respectively.
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Discussion |
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System A activity is defined as the MeAIB uptake that is Na+-dependent, which makes it unlikely that MeAIB diffusing into intercellular spaces or MeAIB nonspecifically bound to the external surfaces of cells contributes significantly to our measurements. Therefore, our measurements represent MeAIB taken up into cells. The use of small primary villous fragments from human placenta has several potential advantages over comparable experimental systems, such as cultured cell lines of placental origin or cytotrophoblast cells. First, the syncytiotrophoblast cells can be studied without prior cell culture, which may markedly alter cell characteristics like transporter expression and activity. Second, the polarization and cell-cell contacts of the studied syncytiotrophoblast in the primary villous fragment are likely to resemble the in vivo conditions. Third, the primary nature of the preparation makes it possible to reliably compare characteristics of villous fragments from normal and complicated pregnancies. However, there are some potential disadvantages in using small villous fragments for studies of nutrient transporters. Because of the cell architecture of the tip of the villous, the external surface of the villous is covered by the syncytiotrophoblast MVM. Therefore, it is reasonable to assume that the measured MeAIB uptake in our study primarily represents the uptake by the syncytiotrophoblast (in particular, its MVM). It should be emphasized that the villous fragment model allows measurements of uptake into the syncytiotrophoblast cell, whereas transcellular transport cannot be addressed directly. However, for active transport processes where the energy-requiring step is localized in the MVM, such as amino acid transport, the uptake across the MVM is an important factor determining the rate of transcellular transport.
It is well established that insulin stimulates system A activity in many nonplacental tissues, such as in cultured human fibroblasts (13) and human skeletal muscle (14). Insulin increased the activity of system A in villous fragments at doses similar to maternal physiological concentrations. These findings are in line with previous studies in cultured trophoblast cells in which MeAIB uptake was stimulated by insulin with concentrations similar to those used in our study (16). These data suggest that insulin has similar effects on system A activity in the placenta as in many other peripheral tissues in promoting neutral amino acid uptake in the postprandial state. Insulin receptors are present in the maternal-facing MVM of human syncytiotrophoblast (30), albeit at lower levels toward term (31), consistent with the possibility that maternal insulin levels may affect placental function. In IUGR, fetal insulin levels are reduced (32), whereas maternal plasma insulin concentrations are unaltered in this pregnancy complication (32). However, placental insulin receptor number has been reported to be markedly decreased in the IUGR placenta (33), raising the possibility that reduced insulin sensitivity in the placenta may be involved in the decreased MVM system A activity in IUGR (2, 3).
Leptin has recently been shown, in an in vitro model, to enhance intestinal peptide transport via the dipeptide transporter PepT1 (34). In the current study, we show that leptin stimulates placental system A; and, to the best of our knowledge, this is the first time that leptin is reported to regulate an amino acid transporter. Because leptin is produced by the human placenta and leptin receptors are present in the syncytiotrophoblast plasma membranes (35, 36, 37), these findings suggest that leptin may be involved in the regulation of placental nutrient transporters in a paracrine/autocrine fashion. Leptin is involved in the regulation of body weight, energy homeostasis, and reproductive processes (38). In pregnancy, leptin may affect the placenta by inducing growth and angiogenesis (35). In the fetus, leptin is suggested to be involved in growth, angiogenesis, hematopoiesis, brain development, and immunity (35). The higher leptin levels in the umbilical vein, compared with umbilical artery, and the marked fall after birth indicate that the human placenta is one of the major sources of leptin in the fetal circulation (35). The functional role of placentally produced leptin remains to be fully established. Human placental leptin is nearly identical to leptin produced by adipose tissue; however, the human placental gene has a specific upstream enhancer that seems to be unique for the placenta (39, 40).
Whereas there is no correlation between maternal leptin levels and birth weight, several studies have reported that umbilical cord blood leptin levels are positively correlated with fetal insulin, birth weight, ponderal index, length, and head circumference (41, 42, 43). Compatible with these associations, small-for-gestational-age babies have low (and large-for-gestational-age babies have high) umbilical plasma leptin concentrations at birth (20, 44).
In the current study, leptin increased system A-mediated amino acid uptake, after 1 h incubation of villous fragments with the hormone, in concentrations somewhat higher than physiological maternal and fetal plasma concentrations (20, 45). However, because of the placental production and secretion of leptin, the hormone concentration at the placental barrier in vivo may be much higher than measured plasma concentrations. These findings suggest that leptin may be involved in the regulation of placental system A and possibly other amino acid transporters. It is possible that this hormone has similar effects in tissues other than placenta. We suggest that leptin, by its effect on placental system A, regulates placental uptake of neutral amino acids and, as a result, may alter amino acid delivery to the fetus. Because of the well-established close relationship among nutrient supply, fetal insulin/IGF-1 levels, and fetal growth, we speculate that one of the mechanisms underlying the positive correlation between leptin levels and fetal growth (16, 44) may be effects on placental nutrient transporters such as system A. The finding that MVM system A activity is reduced in IUGR (3) and increased in pregnancies complicated by diabetes (6), in which accelerated fetal growth is common, provides some indirect support for this hypothesis.
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Footnotes |
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Abbreviations: BM, Basal membrane; EGF, epidermal growth factor; hPL, human placental lactogen; IUGR, intrauterine growth restriction; LDH, lactate dehydrogenase; MeAIB, methylaminoisobutyric acid; MVM, microvillous membrane; SEM, scanning-electron microscopy; TEM, transmission-electron microscopy.
Received August 20, 2002.
Accepted November 22, 2002.
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