Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

Abstract

The 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 (3)H-methyl-D-glucose at D19. By contrast, 10% O2 impaired fetal vascularity, increased barrier thickness and reduced placental (14)C-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.

Figure 1. Schematic diagram of the experimental protocol

Schematic diagram of the experimental protocol and the allocation of pregnant mice between the different treatments, together with the group abbreviations for the treatments used.

Figure 2. Placental transport following exposure to 13% maternal inhalation hypoxia

Materno‐fetal transport of MeGlu and MeAIB and Lz gene expression of glucose (Slc2a1 and Slc2a3) and System A amino acid transporters (Slc38a1, Slc38a2 and Slc38a4) on D16 and D19 of pregnancy following exposure to 13% O₂ inspired air for 5 days from D11 to D16 or D14 to D19 or pair‐feeding normoxic animals to the food intake of mice in 13% O₂ from D11 to D14. Data are the mean ± SEM of placental accumulation of MeGlu (A) and MeAIB (B), placental clearance of MeGlu (C) and MeAIB (D), fetal accumulation of MeGlu (E) and MeAIB (F) and Lz gene expression of glucose transporters (G) and System A amino acid amino acid transporters (H). Normoxic ad libitum fed, white columns, D16N, n = 6–7, D19N, n = 7–13; pair‐fed normoxic animals, striped columns, D16 13% PF, n = 5–7; 13% O₂ hypoxic, D16 13% H, n = 7–10 and D19 13% H, n = 7–13, grey columns. An asterisk denotes significant difference from the normoxic ad libitum fed (N) group at the same age. *P < 0.05 (Student's t test).

Figure 3. Placental transport following exposure to 10% maternal inhalation hypoxia

Materno‐fetal transport of MeGlu and and MeAIB and Lz gene expression of glucose (Slc2a1 and Slc2a3) and System A amino acid transporters (Slc38a1, Slc38a2 and Slc38a4) on D19 of pregnancy following exposure to 10% O₂ inspired air for 5 days from D14 to D19 or pair‐feeding normoxic dams to the food intake of the hypoxic animals from D14 to D19. Data are the mean ± SEM of placental accumulation of MeGlu (A) and MeAIB (B), placental clearance of MeGlu (C) and MeAIB (D), fetal accumulation of MeGlu (E) and MeAIB (F) and Lz gene expression of glucose transporters (G) and System A amino acid transporters (H). Normoxic ad libitum fed, white columns, D19N, n = 7–13; pair‐fed normoxic animals, striped columns, D19 10% PF, n = 7–12; 10% O₂ hypoxic, black columns, D19 10% H, n = 6–14. Columns with different superscript letters are significantly different from each other P < 0.05 (one‐way ANOVA with Bonferroni post hoc tests). The D19N values are identical to those shown in Fig. 2.

Figure 4. Placental insulin/IGF signalling following exposure to 13% maternal inhalation hypoxia

Labyrinthine expression of Igf2 (A) and components of the insulin‐IGF signalling pathway (B and C) on D16 and D19 of pregnancy following exposure to 13% inspired O₂ for 5 days from D11 to D16 or D14 to D19 or pair‐feeding normoxic mice to the food intake of the hypoxic animals from D11 to D16. Data are the mean ± SEM. Normoxic ad libitum fed, white columns, D16N, n = 5–6, D19N, n = 5–9; pair‐fed animals, striped columns, D16 13% PF, n = 5–6; 13% O₂ hypoxic, D16 13% H, n = 5–6 and D19 13% H, n = 5–6, grey columns. On D16, columns with different superscript letters are significantly different from each other P < 0.05 (one‐way ANOVA with Bonferroni post hoc tests). On D19, an asterisk denotes a significant difference from the normoxic ad libitum fed (N) group at the same age. *P < 0.05 (Student's t test).

Figure 5. Placental insulin/IGF signalling following exposure to 10% maternal inhalation hypoxia

Labyrinthine expression of Igf2 (A) and components of the insulin‐IGF signalling pathway (B and C) on D19 of pregnancy following exposure to 10% inspired O₂ for 5 days from D14 to D19 or pair‐feeding normoxic mice to the food intake of the hypoxic animals from D14 to D19. Data are the mean ± SEM. Normoxic ad libitum fed, white columns, D19N, n = 5–9; pair‐fed animals, striped columns, D19 10% PF, n = 5–8; 10% hypoxic, black columns, D19 10% H, n = 5–9. Columns with different superscript letters are significantly different from each other P < 0.05 (one‐way ANOVA with Bonferroni post hoc tests).