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Maternal erythrocyte ENT1–mediated AMPK activation counteracts placental hypoxia and supports fetal growth
Seisuke Sayama, … , Angelo D’Alessandro, Yang Xia
Seisuke Sayama, … , Angelo D’Alessandro, Yang Xia
Published May 21, 2020
Citation Information: JCI Insight. 2020;5(10):e130205. https://doi.org/10.1172/jci.insight.130205.
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Research Article Development Hematology

Maternal erythrocyte ENT1–mediated AMPK activation counteracts placental hypoxia and supports fetal growth

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Abstract

Insufficient O2 supply is frequently associated with fetal growth restriction (FGR), a leading cause of perinatal mortality and morbidity. Although the erythrocyte is the most abundant and only cell type to deliver O2 in our body, its function and regulatory mechanism in FGR remain unknown. Here, we report that genetic ablation of mouse erythrocyte equilibrative nucleoside transporter 1 (eENT1) in dams, but not placentas or fetuses, results in FGR. Unbiased high-throughput metabolic profiling coupled with in vitro and in vivo flux analyses with isotopically labeled tracers led us to discover that maternal eENT1–dependent adenosine uptake is critical in activating AMPK by controlling the AMP/ATP ratio and its downstream target, bisphosphoglycerate mutase (BPGM); in turn, BPGM mediates 2,3-BPG production, which enhances O2 delivery to maintain placental oxygenation. Mechanistically and functionally, we revealed that genetic ablation of maternal eENT1 increases placental HIF-1α; preferentially reduces placental large neutral aa transporter 1 (LAT1) expression, activity, and aa supply; and induces FGR. Translationally, we revealed that elevated HIF-1α directly reduces LAT1 gene expression in cultured human trophoblasts. We demonstrate the importance and molecular insight of maternal eENT1 in fetal growth and open up potentially new diagnostic and therapeutic possibilities for FGR.

Authors

Seisuke Sayama, Anren Song, Benjamin C. Brown, Jacob Couturier, Xiaoli Cai, Ping Xu, Changhan Chen, Yangxi Zheng, Takayuki Iriyama, Baha Sibai, Monica Longo, Rodney E. Kellems, Angelo D’Alessandro, Yang Xia

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Figure 1

Ablation of ENT1 on maternal erythrocytes results in fetal growth restriction.

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Ablation of ENT1 on maternal erythrocytes results in fetal growth restri...
(A) Description of lox-Cre system to generate erythrocyte-specific ENT1-KO mouse. (B) Mating strategy. E1FE female mouse was mated with WT male mouse, and EPO female was used as a control. (C) Representative picture of pups (E18.5) from both EPO and E1FE. (D–F) Graphs showing pup weight, placental weight, and fetus/placenta ratio. Values represent the mean ± SEM. Number of dams used were 9–10. *P < 0.05, ***P < 0.01. Two-tailed Student’s t test was used for statistical analysis.

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