Dataset Information

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-1?; preferentially reduces placental large neutral aa transporter 1 (LAT1) expression, activity, and aa supply; and induces FGR. Translationally, we revealed that elevated HIF-1? 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.

SUBMITTER: Sayama S

PROVIDER: S-EPMC7259528 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Sayama Seisuke S Song Anren A Brown Benjamin C BC Couturier Jacob J Cai Xiaoli X Xu Ping P Chen Changhan C Zheng Yangxi Y Iriyama Takayuki T Sibai Baha B Longo Monica M Kellems Rodney E RE D'Alessandro Angelo A Xia Yang Y

JCI insight 20200521 10

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 co ...[more]

PMID: 32434995

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Project description:Fetal placental macrophages and microglia (resident brain macrophages) have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual's lifetime. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living fetus or neonate is impossible. We sought to test the hypothesis that maternal obesity would prime both placental macrophages and fetal brain microglia to overrespond to an immune challenge, thus providing a window into microglial function using placental cells. Obesity was induced in C57BL/6?J mice using a 60% high-fat diet. On embryonic day 17.5, fetal brain microglia and corresponding CD11b?+?placental cells were isolated from fresh tissue. Cells were treated with media or lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-?) production by stimulated and unstimulated cells was quantified via ELISA. We demonstrate for the first time that the proinflammatory cytokine production of CD11b?+?placental cells is strongly correlated with that of brain microglia (Spearman's ??=?0.73, p?=?0.002) in the setting of maternal obesity. Maternal obesity-exposed CD11b?+?cells had an exaggerated response to LPS compared to controls, with a 5.1-fold increase in TNF-? production in placentas (p?=?0.003) and 3.8-fold increase in TNF-? production in brains (p?=?0.002). In sex-stratified analyses, only male obesity-exposed brains and placentas had significant increase in TNF-? production in response to LPS. Taken together, these data suggest that maternal obesity primes both placental macrophages and fetal brain microglia to overproduce a proinflammatory cytokine in response to immune challenge. Male brain and placental immune response is more marked than female in this setting. Given that fetal microglial priming may impact neuroimmune function throughout the lifespan, these data could provide insight into the male predominance of certain neurodevelopmental morbidities linked to maternal obesity, including cognitive dysfunction, autism spectrum disorder, and ADHD. Placental CD11b+ macrophages may have the potential to serve as an accessible biomarker of aberrant fetal brain immune activation in maternal obesity. This finding may have broader implications for assaying the impact of other maternal exposures on fetal brain development.

Project description:Adenosine monophosphate (AMP)?activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen. While neuroprotective approaches by definition focus on neurons, that are more sensitive under cell stress conditions, astrocytes play an important role in the cerebral energy homeostasis during ischemia. Therefore, the protection of astrocytic cells or other glial cells may contribute to the preservation of neuronal integrity and function. In the present study, it was thus hypothesized that a preventive induction of energy deprivation?activated signaling pathways via AMPK may protect astrocytes from hypoxia and glucose deprivation. Hypoxia?induced cell death was measured in a paradigm of hypoxia and partial glucose deprivation in vitro in the immortalized human astrocytic cell line SVG. Both the glycolysis inhibitor 2?deoxy?d?glucose (2DG) and the AMPK activator A?769662 induced the phosphorylation of AMPK, resulting in mTORC1 inhibition, as evidenced by a decrease in the phosphorylation of the target ribosomal protein S6 (RPS6). Treatment with both 2DG and A?769662 also decreased glucose consumption and lactate production. Furthermore, A?769662, but not 2DG induced an increase in oxygen consumption, possibly indicating a more efficient glucose utilization through oxidative phosphorylation. Hypoxia?induced cell death was profoundly reduced by treatment with 2DG or A?769662. On the whole, the findings of the present study demonstrate, that AMPK activation via 2DG or A?769662 protects astrocytes under hypoxic and glucose?depleted conditions.

Dataset Information

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

Publications

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

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