Chronic Gestational Inflammation: Comparisons of Obesity-Mediated and Preeclampsia-Mediated Placental Inflammation using Transcriptomic and Histological Methods

Abstract

Several obstetrical complications, including maternal obesity (MO) and preeclampsia (PE), are associated with states of chronic gestational inflammation and poor pregnancy outcomes. However, commonalities and/or differences from these divergent chronic inflammatory insults on placental development and function remain elusive. Preliminary work by our group suggests placental NAD+ depletion and subsequent mitochondrial dysfunction may be common pathophysiology features. Using rodent MO- and PE-mediated gestational inflammation models, our aim was exploring common and differing mechanisms through which placental function may become compromised, targeting NAD+ signalling pathways and mitochondrial health. Rodent models of immune-driven PE and MO were previously established in our laboratory. Dams were euthanized at embryonic day 18.5, with assessments of fetal and placental weights. Placentas were then collected and processed for detailed histomorphometry and transcriptomic analyses. Placenta transcriptomics data underwent differential gene expression analysis using DESeq2. Ranked gene set enrichment was conducted using fold change values through GO Annotation Database. Similarly, pathway enrichment was performed through KEGG database (FDR <= 0.10). Fetal growth restriction was observed in both chronic gestational inflammation models. Both MO- and PE-mediated inflammation was associated with reduced placental labyrinth exchange areas. MO-mediated inflammation additionally demonstrated increased junctional zone areas. Transcriptomic analysis revealed enriched inflammatory signalling pathways in both models; the PE model demonstrated profound TNF-Alpha signalling activation while the MO model demonstrated activated IL-1β, IFN-β and TNF signalling, and leukocyte chemotaxis. Likewise, both models demonstrated transcriptomic evidence of mitochondrial dysfunction including downregulated mitochondrial ATP synthesis, oxidative phosphorylation and NADH synthesis pathways. Chronic gestational inflammation is associated with disrupted placental structure and gene expression, culminating in altered fetal growth. While our PE and MO models displayed clinically relevant inflammatory phenotypes, the pathological mechanisms underlying the established placental dysfunction appear distinct. Further studies are needed to clarify the potential role of inflammation-mediated mitochondrial dysfunction in establishing inflammatory placental pathologies to inform design of better therapeutic management of these pregnant population.