A maternal obesogenic diet remodels the uterine microenvironment and impairs placental function

Abstract

Maternal overweight and obesity (i.e., excess adiposity) are risk factors for adverse pregnancy outcomes and long-term maternal and offspring health impairments that are rooted in placental dysfunction. Factors contributing to placental dysfunction in pregnancies affected by excess adiposity are not fully understood. We hypothesized that impaired remodelling of uterine spiral arteries and enhanced inflammatory signalling at the placental interface related to compositional and functional differences in uterine macrophage and natural killer (NK) cells in early pregnancy would contribute to placental hypoxia and impaired vascular maturation. We tested this hypothesis using a mouse model of periconceptional high-fat, high-sucrose (HFHS) diet-induced excess adiposity.

In Chapter 3, we found that HFHS placental tissues were hypoxic and exhibited histological features of malperfusion and inflammation in late gestation. This was accompanied by elevated circulating fetal endocrine and inflammatory mediators. In Chapter 4, we show that diet-induced excess adiposity does not impair spiral artery transformation at mid-gestation but does promote angiogenic and inflammatory shifts related to decidual macrophage and NK cell populations that might contribute to later placental malperfusion. In Chapter 5, we examined the cell-type-specific impacts of excess adiposity using single-cell gene expression analysis. We found that immune and stromal cell populations from HFHS uterine tissues exhibit pro-fibrotic, pro-thrombotic, and potentially immuno-suppressive gene expression changes immediately following embryo implantation. This coincided with immunophenotypic changes in blood monocytes and neutrophils that might be indicative of low-level systemic vascular injury.

Overall, our findings indicate that diet-induced excess adiposity can compromise placental perfusion in the absence of impaired spiral artery remodelling. Altered recruitment and activity of uterine immune cells driven by conditions surrounding excess adiposity likely participate in disrupted uteroplacental perfusion, inflammation, and suboptimal placental function. These data provide new insights into the cellular and molecular mechanisms underlying placental dysfunction in pregnancies affected by overweight and obesity.