Maternal undernourishment impairs murine placental development during pregnancy

Maternal undernourishment (MUN) is a public health issue in developed and underdeveloped countries. There is a wide range of causes, from poor access to nutrition to hyperemesis gravidarum. This condition can adversely affect the development of the placenta, the critical interface between mother and fetus, producing adverse outcomes such as anemia, hemorrhage, developmental delays, and low birth weight (LBW) neonates. We use a murine undernourishment model to examine the consequences of MUN on the placenta at the whole organ and trophoblast (extraembryonic cells that form the placenta) levels. Pregnant dams of this model consumed a combined reduced protein and caloric diet during gestation, resulting in the generation of LBW offspring. We examined placental vascularization (immunostaining), vascular reactivity (myography), and blood perfusion (laser-Doppler flowmetry). We further examined drivers of placental pathology during MUN in both whole placenta and primary trophoblast cells, such as oxidative stress (including mitochondrial), on trophoblast quantity, apoptosis, proliferation, and differentiation. Therapeutic drugs were also investigated to elucidate the pathways involved and as possible interventions. Analysis revealed that MUN reduced placental weight, altered the labyrinth/junctional zone ratio, and compromised overall trophoblast integrity and pool size. Increased oxidative stress production and dysregulated endogenous antioxidant mechanisms contribute to the associated impairments in the MUN placenta. Uterine blood flow, umbilical vein vasoreactivity, placental vascularization, and placental efficiency are also hindered, effects modulated by oxidative stress, including that produced by mitochondrial and toll-like receptor 4-sensitive pathways. MUN upregulates oxidative stress in the placenta, an effect that consequently reduces trophoblast pools while impairing placental development and vascular function. Our study also implicates mitochondrial superoxide production and TLR4 in the detrimental impact of MUN on placental vascular function and development while identifying therapeutic agents as possible add-on interventions.