Maternal erythrocyte ENT1–mediated AMPK activation counteracts placental hypoxia and supports fetal growth
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
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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Research Article Development Hematology

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

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 6

Decreased amino acid uptake by placenta leads to decreased GSH synthesis in both RBCs and placentas in E1FE pregnant mice.

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Decreased amino acid uptake by placenta leads to decreased GSH synthesis...
(A) In vivo flux analysis injecting isotopically labeled 13C15N amino acid mix in both controls and E1FE dams on E17.5, for 24 hours. (B) Glutamine is largely converted to glutamate and GSH in both erythrocytes and placentas. Thus, at the end of point, we compared the plasma 13C15N glutamate and placenta and RBCs GSH. (C) 13C15N-GSH was substantially decreased in the placentas in E1FE compared with the controls. (D) 13C15N-glutamate levels were accumulated in the plasma of E1FE compared with the controls. (E)13C15N-GSH decreased in RBCs of E1FE mice, compared with control. Values represent the mean ± SEM. *P < 0.05 (n = 5). Two-tailed Student’s t test was used for statistical analysis.