Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Fetal growth restriction induces dynamic, sex-specific changes to molecular signatures in the placenta-heart axis of the near-term sheep (128572)

Ashley S Meakin 1 , Doan T Dinh 2 , Jack R T Darby 1 , Stacey L Holman 1 , Darryl L Russell 2 , Janna L Morrison 1
  1. Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
  2. Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia

Background

The interconnected relationship between placenta and heart is critical for establishing lifelong cardiovascular health. Intriguingly, sex differences in the placenta-heart axis in response to pregnancy complications are known; male placentae have impaired adaptability and reserve capacity compared with females, which may exacerbate heart development perturbations. Despite this, the underlying mechanisms that contribute to these responses remain unclear. Therefore, the current study aimed to characterise sex-specific molecular adaptations in the placenta-heart axis of the near-term sheep model of fetal growth restriction (FGR). 

Methods

Left ventricle (LV) and placenta tissue was collected from control and FGR fetuses (n=4/sex/group) at 140d gestation (term=150d) and global gene expression was profiled using RNA-seq. Differential gene expression analysis was performed using the DESeq2 package (genes with adjusted P<0.05, |log2 fold change| ≥1 were considered to be differentially regulated), and pre-ranked gene set enrichment analysis (GSEA) was performed to determine highly represented biological pathways.  

Results

Female FGR placentae had enriched immune signalling (i.e. IFNα and IFNγ response; Inflammatory response) and vascular remodelling capability (i.e. Epithelial mesenchymal transition (EMT); complement; coagulation) when compared with male FGR placentae. In the LV, males increased mitochondrial activity (i.e. oxidative phosphorylation) but reduced immune and cytokine signalling (i.e. IL6/JAK/STAT3 signalling; TNFα via NFκB), growth signalling (i.e. TGFβ signalling, PI3K/AKT/MTOR signalling), structural remodelling (i.e. EMT; apical junction), and metabolism/transport (i.e. Heme metabolism; protein secretion), when compared with females.

Conclusion

These findings indicate that in response to FGR, males are more susceptible to adverse cardiovascular outcomes due to impaired molecular plasticity within the placenta-heart axis. The observed increase in cardiac oxidative phosphorylation in males suggests metabolic overcompensation that is not supported by sufficient structural adaptations in the heart or placenta. Ongoing studies aim to identify upstream regulators driving these observed sex differences in molecular responses to FGR.