@article{10.1172/jci.insight.130205, author = {Seisuke Sayama AND Anren Song AND Benjamin C. Brown AND Jacob Couturier AND Xiaoli Cai AND Ping Xu AND Changhan Chen AND Yangxi Zheng AND Takayuki Iriyama AND Baha Sibai AND Monica Longo AND Rodney E. Kellems AND Angelo D’Alessandro AND Yang Xia}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Maternal erythrocyte ENT1–mediated AMPK activation counteracts placental hypoxia and supports fetal growth}, year = {2020}, month = {5}, volume = {5}, url = {https://insight.jci.org/articles/view/130205}, 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.}, number = {10}, doi = {10.1172/jci.insight.130205}, url = {https://doi.org/10.1172/jci.insight.130205}, }