Maternal high-fat, high-sucrose diet-induced excess adiposity is linked to placental hypoxia and disruption of fetoplacental immune homeostasis in late gestation

Abstract

Maternal excess adiposity (i.e., overweight and obesity) at conception is linked to numerous signs of malperfusion and inflammatory injury in the placenta. Previous reports have suggested that obesity-associated placental malperfusion may trigger a state of fetoplacental hypoxia, contributing to adverse health outcomes within and beyond the perinatal period. However, many previous studies have relied on indirect measures of tissue oxygen saturation, including readouts influenced by external inflammatory stressors. Direct comparisons of tissue oxygen saturation at the uteroplacental interface in pregnancies complicated by excess adiposity are lacking. Here, we used a mouse model of chronic preconception high-fat, high-sucrose (HFHS) diet feeding to model the impacts of an obesogenic milieu on placental oxygenation near term gestation (E17.5). We found that both placental junctional and labyrinth zone tissues were relatively hypoxic in HFHS pregnancies compared to chow-fed controls (CON). However, this was not associated with enhanced HIF-1 expression in labyrinth tissues. Similarly, placentas from CON and HFHS dams did not exhibit gross differences in morphology or vessel density and pericyte coverage. However, HFHS placentas have a greater burden of histopathological lesions, including tissue calcification and fibrinoid deposition within the labyrinth zone. Calcified placental tissue coincided with the destruction of vasculosyncytial membranes and macrophage-dense foci, alongside altered expression of immunomodulatory and chemotactic cytokines within the labyrinth zone proteome, which differed in magnitude with fetal sex. While fetal growth was not markedly affected, fetuses from HFHS pregnancies exhibited higher levels of circulating IL-6, prolactin, CXCL1, and CCL2. Collectively, these data confirm that diet-induced maternal excess adiposity leads to a relative state of placental hypoxia, even in the absence of marked growth restriction or fetal demise. While this hypoxic state is not linked to gross morphological abnormalities, it is associated with a greater histopathological burden indicative of local malperfusion and inflammation, and an altered fetal inflammatory and endocrine milieu in late gestation. These findings provide new insight into mechanisms by which an obesogenic environment during pregnancy compromises placental function and contributes to the long-term programming of chronic disease susceptibility.