The L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health.

Preeclampsia affects ∼2-8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney Mmp9:Timp1 and heart Tnf mRNA expression, indicating increased inflammation. These findings suggest that though administration of L-NAME in mice certainly models key characteristics of preeclampsia during pregnancy, it does not appear to model the adverse increase in cardiovascular disease risk seen in individuals after preeclampsia.

Maternal exercise alters rat fetoplacental stress response: Minimal effects of maternal growth restriction and high-fat feeding.

INTRODUCTION: Fetal growth restriction complicates 10% of pregnancies and increases offspring (F1) risk of metabolic disorders, including obesity and gestational diabetes mellitus (GDM). This disease predisposition can be passed onto the next generation (F2). Importantly, the risk of pregnancy complications in obese women can be exacerbated by a stressful pregnancy. Exercise can reduce adiposity and improve health outcomes in obese women and those with GDM. This study investigated the impacts of maternal growth restriction, obesity, exercise, and stress on fetal and placental endocrine function. METHODS: Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in F0 Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat (HFD) diet from weaning and, at 16 weeks, were randomly allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised only during pregnancy (PregEx). Females were mated and further randomly allocated to either undergo (Stress), or not undergo (Unstressed), physiological measurements during pregnancy. On E20, F2 fetal plasma (steroid hormones), tissues (brain, liver), and placentae (morphology, stress genes) were collected. RESULTS: Maternal growth restriction and high-fat feeding had minimal impact on fetoplacental endocrine function. PregEx and Exercise increased cross-sectional labyrinth and junctional zone areas. PregEx, but not Exercise, increased fetal deoxycorticosterone concentrations and reduced placental Hsd11b2 and Nr3c2 gene abundance. Maternal stress increased fetal corticosterone concentrations in Sedentary HFD dams and increased placental cross-sectional areas in PregEx mothers. DISCUSSION: PregEx and Stress independently dysregulates the endocrine status of the developing fetus, which may program future disease.

Placental adaptations to micronutrient dysregulation in the programming of chronic disease.

Poor nutrition during pregnancy is known to impair foetal development and increase the risk of chronic disease in offspring. Both macronutrients and micronutrients are required for a healthy pregnancy although significantly less is understood about the role of micronutrients in the programming of chronic disease. This is despite the fact that modern calorie rich diets are often also deficient in key micronutrients. The importance of micronutrients in gestational disorders is clearly understood but how they impact long term disease in humans requires further investigation. In contrast, animal studies have demonstrated how diets high or low in specific micronutrients influence offspring physiology. Many of these studies highlight the importance of the placenta in determining disease risk. This review will explore the effects of individual vitamins, minerals and trace elements on offspring disease outcomes and discuss several key placental adaptations that are affected by multiple micronutrients. These placental adaptations include micronutrient induced dysregulation of oxidative stress, altered methyl donor availability and its impact on epigenetic mechanisms as well as endocrine dysfunction. Critical gaps in our current knowledge and the relative importance of different micronutrients at different gestational ages will also be highlighted. Finally, this review will discuss the need for further studies to characterise the micronutrient status of Australian women of reproductive age and correlate micronutrient status to placental adaptations, pregnancy complications and offspring disease.

Maternal exercise and growth restriction in rats alters placental angiogenic factors and blood space area in a sex-specific manner.

Fetal growth and development are dependent on adequate placental nutrient transfer. The surface area of the placental villous network is a key determinant of nutrient exchange, which is regulated by vasculogenic and angiogenic factors. These factors are altered by intrauterine growth restriction (IUGR) and maternal obesity in both the first (F1) and second (F2) generations. We investigated the impact of endurance exercise in IUGR dams fed a High-fat diet on placental vasculogenesis and angiogenesis. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat diet from weaning, and at 16 weeks were further allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) and F2 placentae collected at E20. Maternal Restriction, High-fat feeding and Exercise had a minimal impact on placental regulators of vasculogenesis and angiogenesis. However, Restriction increased placental labyrinth tissue area in Chow-fed dams. PregEx induced overt adaptations, including increased VEGFA and decreased PLGF protein expression, and reduced blood space area. These alterations were sex-dependent and associated with alterations in miRNA27a, a known regulator of VEGF translation. These data highlight that maternal exercise initiated during pregnancy (PregEx) causes alterations in placental vasculogenesis and angiogenesis in a sex-dependent manner, with minimal Restriction and maternal diet effects. However, further investigation is required to determine if these adaptations are beneficial or harmful for maternal and fetoplacental outcomes.

Biomarkers of oxidative stress in pregnancy complications.

Pregnancy complications including pre-eclampsia, gestational-diabetes mellitus, preterm birth and intrauterine growth restriction can cause acute and chronic health problems for the mother and lead to fetal loss or dysregulation of infant physiology. The human placenta is susceptible to oxidative stress and oxidative damage in early gestation contributes to the onset of these conditions later in pregnancy. Current methods of predicting pregnancy complications are limited and although a large number of factors are associated with disease progression, few biomarkers have been used to aid in disease diagnosis early in gestation. This review discusses the detection of oxidative stress markers in biological fluids and highlights the need for further studies to validate their use in the prediction or diagnosis of pregnancy disorders.