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. 2020 Jan 1;128(1):127-133.
doi: 10.1152/japplphysiol.00691.2019. Epub 2019 Dec 5.

Effect of high altitude on human placental amino acid transport

Owen R Vaughan  1 , Fredrick Thompson  1 , Ramón A Lorca  1 , Colleen G Julian  2 , Theresa L Powell  1   3 , Lorna G Moore  1 , Thomas Jansson  1
Affiliations

Effect of high altitude on human placental amino acid transport

Owen R Vaughan et al. J Appl Physiol (1985). .

Abstract

Women residing at high altitudes deliver infants of lower birth weight than at sea level. Birth weight correlates with placental system A-mediated amino acid transport capacity, and severe environmental hypoxia reduces system A activity in isolated trophoblast and the mouse placenta. However, the effect of high altitude on human placental amino acid transport remains unknown. We hypothesized that microvillous membrane (MVM) system A and system L amino acid transporter activity is lower in placentas of women living at high altitude compared with low-altitude controls. Placentas were collected at term from healthy pregnant women residing at high altitude (HA; >2,500 m; n = 14) or low altitude (LA; <1,700 m; n = 14) following planned, unlabored cesarean section. Birth weight, but not placenta weight, was 13% lower in HA pregnancies (2.88 ± 0.11 kg) compared with LA (3.30 ± 0.07 kg, P < 0.01). MVM erythropoietin receptor abundance, determined by immunoblot, was greater in HA than in LA placentas, consistent with lower placental oxygen levels at HA. However, there was no effect of altitude on MVM system A or L activity, determined by Na+-dependent [14C]methylaminoisobutyric acid uptake and [3H]leucine uptake, respectively. MVM abundance of glucose transporters (GLUTs) 1 and 4 and basal membrane GLUT4 were also similar in LA and HA placentas. Low birth weights in the neonates of women residing at high altitude are not a consequence of reduced placental amino acid transport capacity. These observations are in general agreement with studies of IUGR babies at low altitude, in which MVM system A activity is downregulated only in growth-restricted babies with significant compromise.NEW & NOTEWORTHY Babies born at high altitude are smaller than at sea level. Birth weight is dependent on growth in utero and, in turn, placental nutrient transport. We determined amino acid transport capacity in placentas collected from women resident at low and high altitude. Altitude did not affect system A amino acid transport across the syncytiotrophoblast microvillous membrane, suggesting that impaired placental amino acid transport does not contribute to reduced birth weight in this high-altitude population.

Keywords: fetal growth; glucose transporter; maternal-fetal exchange; trophoblast.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
Relationship between maternal altitude of residence and birth weight. Symbols indicate individual low-altitude (●) and high-altitude (○) subjects. Crossed circles indicate placentas collected from pregnancies complicated by intrauterine growth restriction; r and P values for Pearson correlation are given.
Fig. 2.
Fig. 2.
Effect of high altitude on microvillous membrane erythropoietin receptor. Representative image of capillary electrophoresis bands and protein band abundance, normalized to vinculin, in placentas collected at low altitude (L; n = 14) and high altitude (H; n = 14). **P < 0.01 vs. low altitude by Mann-Whitney U-test. Symbols indicate individual subjects; bars are means ± SD. Crossed circles indicate placentas collected from pregnancies complicated by intrauterine growth restriction.
Fig. 3.
Fig. 3.
Effect of high altitude on microvillous membrane amino acid transport capacity. A and C: system A activity determined by Na+-dependent uptake of [14C]methylaminoisobutyric acid ([14C]MeAIB). B and D: system L activity determined by mediated [3H]leucine uptake. A and B: net uptake time course over 30 s of incubation with tracer (n = 5 placentas). Dashed line shows linear regression of net amino acid uptake over 20 s. C and D: rates of system A and system L net uptake were determined at 10 s of tracer incubation and did not differ in low- (n = 14) vs. high-altitude placentas (n = 14). Symbols indicate individual subjects; bars are means ± SD. Crossed circles indicate placentas collected from pregnancies complicated by intrauterine growth restriction.
Fig. 4.
Fig. 4.
Effect of high altitude on microvillous and basal plasma membrane glucose transporter abundance. A and B: representative blots and relative abundance of glucose transporter 1 (GLUT1) in microvillous (MVM) and basal plasma membranes (BM). C: GLUT4 in basal plasma membranes was similar in low-altitude (n = 13) and high-altitude (n = 14) placentas. Symbols indicate individual subjects; bars are means ± SD. Crossed circles indicate placentas collected from pregnancies complicated by intrauterine growth restriction. Means ± SD. Protein abundance is expressed relative to total protein stained with amido black.
Fig. 5.
Fig. 5.
Effect of high altitude on eukaryotic initiation factor-2α (EIF2α) signaling. A: representative blots and relative abundance of total and phosphorylated EIF2α, activating transcription factor 4 (ATF4), and total and phosphorylated general control nonderepressible 2 (GCN2) in homogenates of low-altitude (L; n = 13) and high-altitude (H; n = 14) placentas. Means ± SD. *P < 0.05 vs. low altitude by Mann-Whitney U-test. B: representative capillary electrophoresis image and relative abundance of phosphorylated EIF2α normalized to vinculin in homogenates of high- (n = 14) compared with low-altitude (n = 13) placentas. Symbols indicate individual subjects; bars are means ± SD. Crossed circles indicate placentas collected from pregnancies complicated by intrauterine growth restriction. C–F: correlations of EPO-R, EIF2α, and nutrient transporter activity/abundance in the syncytiotrophoblast membranes; r and P values for Pearson correlations are given (n = 27). ●, Low altitude; ○, high altitude.
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