Placental insufficiency induces a sexually dimorphic response in the expression of cardiac growth and metabolic signalling molecules upon exposure to a postnatal western diet in guinea pigs

Abstract

There is a strong relationship between low birth weight (LBW) and an increased risk of developing cardiovascular disease (CVD). In postnatal life, LBW offspring are becoming more commonly exposed to the additional independent CVD risk factors, such as an obesogenic diet. However, how an already detrimentally programmed LBW myocardium responds to a secondary insult, such as an obesogenic diet (western diet; WD), during postnatal life is ill defined. Herein, we aimed to determine in a pre-clinical guinea pig model of CVD, both the independent and interactive effects of LBW and a postnatal WD on the molecular pathways that regulate cardiac growth and metabolism. Uterine artery ablation was used to induce placental insufficiency (PI) in pregnant guinea pigs to generate LBW offspring. Normal birth weight (NBW) and LBW offspring were weaned onto either a Control diet or WD. At ˜145 days after birth (young adulthood), male and female offspring were humanely killed, the heart weighed and left ventricle tissue collected. The mRNA expression of signalling molecules involved in a pathological hypertrophic and fibrotic response was increased in the myocardium of LBW male, but not female offspring, fed a WD as was the mRNA expression of transcription factors involved in fatty acid oxidation. The mRNA expression of glucose transporters was downregulated by LBW and WD in male, but not female hearts. This study has highlighted a sexually dimorphic cardiac pathological hypertrophic and fibrotic response to the secondary insult of postnatal WD consumption in LBW offspring.

Development of a novel Guinea Pig model producing transgenerational endothelial transcriptional changes driven by maternal food restriction and a second metabolic insult of high fat diet

“…Despite the smaller number of affected transcripts, the restricted diet F1 comparison (PR-C versus PR-H) produced a number of genes associated with GO terms including: Positive regulation of cholesterol biosynthetic process ( Abcg1 , Srebf1 ), Negative regulation of cholesterol storage ( Abca1 , Abcg1 ), and Regulation of cholesterol biosynthetic process ( Abca1 , Srebf1 , Scd1 ). Our finding of fewer transcripts associated with the dietary restriction arm of the F1 generation may seem inconsistent with previous reports that indicate a worsening of cardiovascular disease in offspring where maternal dietary restriction occurred ( Thompson et al, 2014 ; Darby et al, 2022 ). However, it is important to note that our subjects only consumed their HFD for 12 weeks.…”

Metabolic and fecal microbial changes in adult fetal growth restricted mice

“… 49 Growth-restricted male guinea pigs had a more adverse response to a high fat diet. 50 Sexual dimorphism has also been noted in pig 17 and non-human primate 51 , 52 models of FGR. In humans, fetuses respond to intrauterine exposures in a sexually dimorphic manner, which may impact postnatal outcomes.…”

Exercise and hypoxia unmask pulmonary vascular disease and right ventricular dysfunction in a 10‐ to 12‐week‐old swine model of neonatal oxidative injury

“…In this study, we focused on the influence of NOI on a young, developing cardiopulmonary system, thereby simplifying the complexity of the hits. Other studies have used (premature) sheep, thereby including infection, placental insufficiency, maternal undernutrition or chronic hypoxaemia as a factor, but with more limited follow-up duration (Botting et al, 2014;Darby et al, 2018Darby et al, , 2020Darby et al, , 2022Vrselja et al, 2022). More complex models with multiple hits clearly have the advantage that they mimic the clinical situation more closely.…”