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Cardiovascular dysfunctions complicate 10–20% of pregnancies, increasing the risk for postpartum mortality. Various gestational insults, including preeclampsia are reported to be associated with adverse maternal cardiovascular outcomes. One such insult, gestational hyperandrogenism increases the risk for preeclampsia and other gestational morbidities but its impact on postpartum maternal health is not well known. We hypothesize that gestational hyperandrogenism such as testosterone (T) excess will adversely impact the maternal heart in the postpartum period. Pregnant ewes were injected with T propionate from day 30 to day 90 of gestation (term 147 days). Three months postpartum, echocardiograms, plasma cytokine profiles, cardiac morphometric, and molecular analysis were conducted [control (C) n = 6, T-treated (T) n = 7 number of animals]. Data were analyzed by two-tailed Student's t test and Cohen's effect size (d) analysis. There was a nonsignificant large magnitude decrease in cardiac output (7.64 ± 1.27 L/min vs. 10.19 ± 1.40, P = 0.22, d = 0.81) and fractional shortening in the T ewes compared with C (35.83 ± 2.33% vs. 41.50 ± 2.84, P = 0.15, d = 0.89). T treatment significantly increased 1) left ventricle (LV) weight-to-body weight ratio (2.82 ± 0.14 g/kg vs. 2.46 ± 0.08) and LV thickness (14.56 ± 0.52 mm vs. 12.50 ± 0.75), 2) proinflammatory marker [tumor necrosis factor-alpha (TNF-α)] in LV (1.66 ± 0.35 vs. 1.06 ± 0.18), 3) LV collagen (Masson's Trichrome stain: 3.38 ± 0.35 vs. 1.49 ± 0.15 and Picrosirius red stain: 5.50 ± 0.32 vs. 3.01 ± 0.23), 4) markers of LV apoptosis, including TUNEL (8.3 ± 1.1 vs. 0.9 ± 0.18), bcl-2-associated X protein (Bax)+-to-b-cell lymphoma 2 (Bcl2)+ ratio (0.68 ± 0.30 vs. 0.13 ± 0.02), and cleaved caspase 3 (15.4 ± 1.7 vs. 4.4 ± 0.38). These findings suggest that gestational testosterone excess adversely programs the maternal LV, leading to adverse structural and functional consequences in the postpartum period. NEW & NOTEWORTHY: Using a sheep model of human translational relevance, this study provides evidence that excess gestational testosterone exposure such as that seen in hyperandrogenic disorders adversely impacts postpartum maternal hearts. [ABSTRACT FROM AUTHOR]

Background: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later‐life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype. Material and methods: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes. Results: A significant decrease in activities of mitochondrial complexes I, II‐III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy‐related protein content (p62, beclin‐I, LC3‐I, LC3‐II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO. Conclusions: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases. [ABSTRACT FROM AUTHOR]

Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11β hydroxysteroid dehydrogenase 2 (11β-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11β-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11β-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11β-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11β-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11β-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11β-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses. [ABSTRACT FROM AUTHOR]

Perturbed in utero hormone milieu leads to intrauterine growth retardation (IUGR), a known risk factor for left ventricular (LV) dysfunction later in life. Gestational testosterone (T) excess predisposes offspring to IUGR and leads to LV myocardial disarray and hypertension in adult females. However, the early impact of T excess on LV programming and if it is female specific is unknown. LV tissues were obtained at day 90 gestation from days 30-90 T-treated or control fetuses ( n = 6/group/sex) and morphometric and molecular analyses were conducted. Gestational T treatment increased cardiomyocyte number only in female fetuses. T excess upregulated receptor expression of insulin and insulin-like growth factor. Furthermore, in a sex-specific manner, T increased expression of phosphatidylinositol 3-kinase ( PI3K ) while downregulating phosphorylated mammalian target of rapamycin ( pmTOR )-to- mTOR ratio suggestive of compensatory response. T excess 1 ) upregulated atrial natriuretic peptide ( ANP ) and brain natriuretic peptide ( BNP ), markers of stress and cardiac hypertrophy and 2 ) upregulated estrogen receptors1 (ESR1) and 2 (ESR2), but not in androgen receptor ( AR ). Thus, gestational T excess upregulated markers of cardiac stress and hypertrophy in both sexes while inducing cardiomyocyte hyperplasia only in females, likely mediated via insulin and estrogenic programming. NEW & NOTEWORTHY The present study demonstrates sex-specific effects of gestational T excess between days 30 and 90 of gestation on the cardiac phenotype. Furthermore, the sex-specific programming is likely secondary to perturbation in both estrogen and insulin signaling pathways collectively. These findings are supportive of the role of androgen excess to serve as early biomarkers of CVD and could be critical in identifying therapeutic targets for LV hypertrophy and predict long-term CVD.