Effects of excess thromboxane A2 on placental development and nutrient transporters in a Mus musculus model of fetal growth restriction†

Abstract

Hypertensive disease of pregnancy (HDP) with placental insufficiency is the most common cause of fetal growth restriction (FGR) in the developed world. Despite the known negative consequences of HDP both to the mother and fetus, little is known about the longitudinal placental changes that occur as HDP progresses in pregnancy. This is because longitudinal sampling of human placentae during each gestation is impossible. Therefore, using a mouse model of thromboxane A2-analog infusion to mimic human HDP in the last trimester, we calculated placental efficiencies based on fetal and placental weights; quantified spongiotrophoblast and labyrinth thicknesses and vascular density within these layers; examined whether hypoxia signaling pathway involving vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1, VEGFR2) and matrix metalloproteinases (MMPs) contributed to vascular change; and examined nutrient transporter abundance including glucose transporters 1 and 3 (GLUT1, GLUT3), neutral amino acid transporters 1, 2, and 4 (SNAT1, SNAT2, and SNAT4), fatty acid transporters 2 and 4 (FATP2, FATP4), and fatty acid translocase (CD36) from embryonic day 15.5 to 19 in a 20-day C57Bl/6J mouse gestation. We conclude that early-to-mid gestation hypertensive placentae show compensatory mechanisms to preserve fetal growth by increasing placental efficiencies and maintaining abundance of important nutrient transporters. As placental vascular network diminishes over late hypertension, placental efficiency diminishes and fetal growth fails. Neither hypoxia signaling pathway nor MMPs mediated the vascular diminution in this model. Hypertensive placentae surprisingly exhibit a sex-differential expression of nutrient transporters in late gestation despite showing fetal growth failure in both sexes.

Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

“…While sexual dimorphism in human placental nutrient transporters has not yet been comprehensively described across all types, increasing evidence suggests that placental sex drives how nutrient transporters adapt to adverse environments. Elevated placental fatty acid transporters in males have been reported in rodent models of both maternal high-fat and high-salt consumption [ 54 ] and thromboxane A2-induced gestational hypertension [ 55 ]. Such increases, however, may be problematic to the placenta as increased lipids can result in lipotoxicity, a phenomenon that has been described in placentae from obese mothers [ 56 ].…”

Intrauterine growth restriction causes cellular, molecular, and behavioral deficits consistent with abnormal dentate gyrus neurogenesis in mice

“…Such a lack of knowledge not only impedes our ability to counsel families about mechanisms of disease, but also hinders our ability to design therapy targeted at improving learning and memory function. Recognizing this gap, our laboratory developed a mouse model of IUGR that closely mimics human IUGR (11,12,(18)(19)(20) in order to dissect the functional, cellular, and molecular phenotypes of the developing IUGR hippocampus.…”

“…Additionally, IUGR offspring exhibited smaller weight gain from E17.5 to E19 and were 15% symmetrically growth restricted at birth compared to sham controls (11,12).…”

“…We therefore employed our laboratory's mouse model of IUGR induced by thromboxane A 2 -analog infusion to dissect the cellular and molecular events that are disrupted during embryonic DG neurogenesis (11,12). We first performed a battery of behavioral assays to establish the functional deficits in this model.…”

Intrauterine Growth Restriction Followed by Oxygen Support Uniquely Interferes with Genetic Regulators of Myelination

“…Thromboxane A2 (TXA2), is a vasoconstrictor overly expressed in mothers whose pregnancies are complicated by hypertension, cigarette smoking, and poorly controlled diabetes (McAdam et al, 2005;Hayakawa et al, 2006;Fung et al, 2011;Gibbins et al, 2018). Infusion of TXA2-analog U-46619 has been demonstrated to result in placental vasculature reduction, suggesting placental vascular insufficiency, similar to human placental pathology resulting in IUGR (Gibbins et al, 2018). This model does not require invasive surgery and it is physiologically relevant to human IUGR pregnancies.…”