Maternal hypoxia decreases capillary supply and increases metabolic inefficiency leading to divergence in myocardial oxygen supply and demand

Maternal hypoxia is associated with a decrease in left ventricular capillary density while cardiac performance is preserved, implying a mismatch between metabolism and diffusive exchange. We hypothesised this requires a switch in substrate metabolism to maximise efficiency of ATP production from limited oxygen availability. Rat pups from pregnant females exposed to hypoxia (FIO2=0.12) at days 10-20 of pregnancy were grown to adulthood and working hearts perfused ex vivo. 14 C-labelled glucose and 3 H-palmitate were provided as substrates and metabolism quantified from recovery of 14CO2 and 3 H2O, respectively. Hearts of male offspring subjected to Maternal Hypoxia showed a 20% decrease in cardiac output (P<0.05), despite recording a 2-fold increase in glucose oxidation (P<0.01) and 2.5-fold increase (P<0.01) in palmitate oxidation. Addition of insulin to Maternal Hypoxic hearts, further increased glucose oxidation (P<0.01) and suppressed palmitate oxidation (P<0.05), suggesting preservation in insulin signalling in the heart. In vitro enzyme activity measurements showed that Maternal Hypoxia increased both total and the active component of cardiac pyruvate dehydrogenase (both P<0.01), although pyruvate dehydrogenase sensitivity to insulin was lost (NS), while citrate synthase activity declined by 30% (P<0.001) and acetyl-CoA carboxylase activity was unchanged by Maternal Hypoxia, indicating realignment of the metabolic machinery to optimise oxygen utilisation. Capillary density was quantified and oxygen diffusion characteristics examined, with calculated capillary domain area increased by 30% (P<0.001). Calculated metabolic efficiency decreased 4-fold (P<0.01) for Maternal Hypoxia hearts. Paradoxically, the decline in citrate synthase activity and increased metabolism suggest that the scope of individual mitochondria had declined, rendering the myocardium potentially more sensitive to metabolic stress. However, decreasing citrate synthase may be essential to preserve local PO2, minimising regions of hypoxia and hence maximising the area of myocardium able to preserve cardiac output following maternal hypoxia

Systemic Maternal Inflammation and Neonatal Hyperoxia Induces Remodeling and Left Ventricular Dysfunction in Mice

The impact of the neonatal environment on the development of adult cardiovascular disease is poorly understood. Systemic maternal inflammation is linked to growth retardation, preterm birth, and maturation deficits in the developing fetus. Often preterm or small-for-gestational age infants require medical interventions such as oxygen therapy. The long-term pathological consequences of medical interventions on an immature physiology remain unknown. In the present study, we hypothesized that systemic maternal inflammation and neonatal hyperoxia exposure compromise cardiac structure, resulting in LV dysfunction during adulthood.Pregnant C3H/HeN mice were injected on embryonic day 16 (E16) with LPS (80 µg/kg; i.p.) or saline. Offspring were placed in room air (RA) or 85% O(2) for 14 days and subsequently maintained in RA. Cardiac echocardiography, cardiomyocyte contractility, and molecular analyses were performed. Echocardiography revealed persistent lower left ventricular fractional shortening with greater left ventricular end systolic diameter at 8 weeks in LPS/O(2) than in saline/RA mice. Isolated cardiomyocytes from LPS/O(2) mice had slower rates of contraction and relaxation, and a slower return to baseline length than cardiomyocytes isolated from saline/RA controls. α-/β-MHC ratio was increased and Connexin-43 levels decreased in LPS/O(2) mice at 8 weeks. Nox4 was reduced between day 3 and 14 and capillary density was lower at 8 weeks of life in LPS/O(2) mice.These results demonstrate that systemic maternal inflammation combined with neonatal hyperoxia exposure induces alterations in cardiac structure and function leading to cardiac failure in adulthood and supports the importance of the intrauterine and neonatal milieu on adult health

Effects of 2-methoxyestradiol administration in mouse models purported to show signs of preeclampsia and fetal growth restriction

Plasma concentration of 2-methoxyestradiol (2-ME) and placental expression of catechol-O-methyltransferase(COMT) are elevated in normal pregnancy, but reduced in women with preeclampsia (PE). Women with PE and fetal growth restriction (FGR)exhibit decreased utero-placental blood flow. Catechol-O-methyltransferase knockout mice (COMT-/-) and female CBA/J mice mated with male DBA/2 mice (CBA/J × DBA/2)show many signs of PE during pregnancy and deliver growth-restricted pups. 2-ME is known to induce significant vasorelaxation of uterine arteries from pregnant mice. We hypothesized that 2-ME administration during pregnancy will lead to an increase in uterine artery blood flow velocity in COMT-/- and CBA/J × DBA/2 mice and therefore ameliorate PE-like signs and rescue fetal growth in these animal models. Pregnant COMT-/- and their controls (C57BL/6),and CBA/J × DBA/2 and their controls (CBA/J × BALB/c),were injected subcutaneously daily with 10 ng of 2-ME or vehicle (olive oil) from gestational day (GD) 12.5 to 17.5. There was no significant effect of genotype/strain or treatment on maternal blood pressure, uterine artery blood flow velocity or fetal growth. A perturbed phenotype only occurred in the COMT-/- mice in regard to umbilical artery flow velocity, proteinuria and 2-ME levels. Administration of 2-ME led to normalization ofumbilical artery blood flow velocity and proteinuria in COMT-/- mice. The utility of 2-ME in cases of PE and FGR needs to be further explored in PE models that exhibit more severe disease phenotypes