Maternal erythrocyte ENT1-mediated oxygen delivery is necessary for adequate placental oxygenation and fetal growth

Abstract

Background: Insufficient oxygen supply is closely associated with the pathophysiology of fetal growth restriction (FGR). Although the erythrocyte is the most abundant and only cell type to deliver oxygen in our body, its function and regulatory mechanism in FGR remains unknown. Recently, intracellular adenosine uptake by equilibrative nucleoside transporter 1 (ENT1), a key adenosine transporter predominantly expressed in erythrocytes, was reported to be crucial for erythrocytes to deliver oxygen. Current study was aimed to investigate the involvement of erythrocytes’ oxygen delivering capacity in maintaining fetal growth by focusing on erythrocyte ENT1. Methods and Results: Conditional knockout mice with erythrocyte-specific gene deletion of ENT1 were utilized in this study. These mice indeed showed reduction in oxygen delivering capacity during pregnancy compared to control mice. We found that genetic ablation of mouse erythrocyte ENT1 in dams results in FGR without showing any maternal features of preeclampsia. Unbiased highthroughput metabolic profiling led us to discover that these transgenic mice have lower amino acid concentration in the placenta and higher amino acid concentration in the serum compared to the control dams. Mechanistically and functionally, we revealed genetic ablation of maternal erythrocyte