9 Impact of placental insufficiency-induced growth restriction on the fetal sheep heart transcriptome

Abstract Abstract: Introduction Fetal growth restriction (FGR) often occurs with placental insufficiency and profoundly adversely affects the developing heart. Previously, we reported that FGR fetal sheep had fewer total numbers of cardiomyocytes, which were smaller and less mature, along with lower ventricular mitochondrial respiration compared to normally growing control fetuses. However, the molecular pathways responsible for producing this phenotype remain unknown. Objectives We performed transcriptomic analysis to identify deregulated biological processes and pathways in the FGR fetal heart compared to normally growing control (CON) sheep fetuses. Methods Left and right ventricles (LV, RV) were harvested from FGR and CON fetal sheep (n = 14/group) at 0.9 gestation. RNA was extracted from frozen tissue, and RNA-seq was performed. Differentially expressed genes were used to determine enriched biological processes and KEGG pathways. An FDR < 0.05 was considered significant. Results Combining LV and RV, we identified 2386 up-regulated and 2112 down-regulated genes (FGR vs. CON). FGR induced up-regulation of the HIF-1 signaling pathway and angiogenic processes, and down-regulation of biological processes involved in cell division, cell cycle, protein phosphorylation, insulin signaling, steroid biosynthesis, TCA cycle, and lipid metabolism compared to CON. Conclusions Increases in hypoxia-responsive and angiogenic pathways in the FGR fetal heart might be a response to lower oxygen levels to increase vascular growth. Simultaneously, the inhibition of cell proliferation, metabolism, and hormonal signaling processes indicates a suppression of growth-promoting and energy-intensive activities, consistent with a smaller heart with reduced oxidative capacity observed in FGR. (Supported by NIH UL1TR002535)