Key points Hypoxia is a major cause of fetal growth restriction, particularly at high altitude, although little is known about its effects on placental phenotype and resource allocation to fetal growth.In the present study, maternal hypoxia induced morphological and functional changes in the mouse placenta, which depended on the timing and severity of hypoxia, as well as the degree of maternal hypophagia.Hypoxia at 13% inspired oxygen induced beneficial changes in placental morphology, nutrient transport and metabolic signalling pathways associated with little or no change in fetal growth, irrespective of gestational age.Hypoxia at 10% inspired oxygen adversely affected placental phenotype and resulted in severe fetal growth restriction, which was due partly to maternal hypophagia.There is a threshold between 13% and 10% inspired oxygen, corresponding to altitudes of ∼3700 m and 5800 m, respectively, at which the mouse placenta no longer adapts to support fetal resource allocation. This has implications for high altitude human pregnancies. AbstractThe placenta adapts its transport capacity to nutritional cues developmentally, although relatively little is known about placental transport phenotype in response to hypoxia, a major cause of fetal growth restriction. The present study determined the effects of both moderate hypoxia (13% inspired O2) between days (D)11 and D16 or D14 and D19 of pregnancy and severe hypoxia (10% inspired O2) from D14 to D19 on placental morphology, transport capacity and fetal growth on D16 and D19 (term∼D20.5), relative to normoxic mice in 21% O2. Placental morphology adapted beneficially to 13% O2; fetal capillary volume increased at both ages, exchange area increased at D16 and exchange barrier thickness reduced at D19. Exposure to 13% O2 had no effect on placental nutrient transport on D16 but increased placental uptake and clearance of 3H‐methyl‐d‐glucose at D19. By contrast, 10% O2 impaired fetal vascularity, increased barrier thickness and reduced placental 14C‐methylaminoisobutyric acid clearance at D19. Consequently, fetal growth was only marginally affected in 13% O2 (unchanged at D16 and −5% at D19) but was severely restricted in 10% O2 (−21% at D19). The hypoxia‐induced changes in placental phenotype were accompanied by altered placental insulin‐like growth factor (IGF)‐2 expression and insulin/IGF signalling, as well as by maternal hypophagia depending on the timing and severity of the hypoxia. Overall, the present study shows that the mouse placenta can integrate signals of oxygen and nutrient availability, possibly through the insulin‐IGF pathway, to adapt its phenotype and optimize maternal resource allocation to fetal growth during late pregnancy. It also suggests that there is a threshold between 13% and 10% inspired O2 at which these adaptations no longer occur.
Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110α in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α resulted in viable fetuses, abnormal placental development and a failure of the placenta to transport sufficient nutrients to match fetal demands for growth. Using RNA-seq we identified genes downstream of p110α in the trophoblast that are important in adapting placental phenotype. Using CRISPR/Cas9 we showed loss of p110α differentially affects gene expression in trophoblast and embryonic stem cells. Our findings reveal important, but distinct roles for p110α in the different compartments of the conceptus, which control fetal resource acquisition and growth.
32Previous studies suggest that the placental supply of nutrients to the fetus adapts according to fetal 33 demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier 34 work in mice has revealed that loss of the phosphoinositide 3-kinase p110α impairs feto-placental growth 35 but placental nutrient supply is adaptively increased. Here we explore the role of p110α in the epiblast-36 derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental 37 development and transfer function. Using conditional gene manipulations to knock-down p110α either by 38 ~50% or ~100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is 39 essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of 40 fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and 41 impaired placental formation and nutrient transport. Loss of trophoblast p110α also resulted in abnormal 42 placental development, although fetuses were viable. However, in response to complete loss of 43 trophoblast p110α, the placenta failed to transport sufficient amino acid to match fetal demands for 44 growth. Using RNA-seq, we identified several genes downstream of p110α in the trophoblast that are 45 important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 46 genome targeting showed that loss of p110α differentially affects the expression of genes in trophoblast 47 and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110α signaling in the 48 2 different compartments of the conceptus, which control fetal resource acquisition and ultimately affect 49 healthy growth. 50 51
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