Severe Feto-Placental Abnormalities Precede the Onset of Hypertension and Proteinuria in a Mouse Model of Preeclampsia1

Abstract

Preeclampsia is a prevalent and potentially devastating disorder of pregnancy. Characterized by a sudden spike in blood pressure and urinary protein levels, it is associated with significant obstetric complications. BPH/5 is an inbred mouse model of preeclampsia with borderline hypertension before pregnancy. BPH/5 mice develop hypertension, proteinuria, and endothelial dysfunction during late gestation (after E14.5). We hypothesized that BPH/5 mice might exhibit early feto-placental abnormalities before the onset of maternal disease. All placental cell lineages were present in BPH/5 mice. However, the fetal and placental weights were reduced, with abnormalities in all the placental zones observed starting early in gestation (E9.5-E12.5). The fractional area occupied by the junctional zone was significantly reduced at all gestational timepoints. Markedly fewer CDKN1C-stained trophoblasts were seen invading the proximal decidual zone, and this was accompanied by reductions in Cdkn1c gene expression. Trophoblast giant cell morphology and cytokeratin staining were not altered, although the mRNA levels of several giant cell-specific markers were significantly downregulated. The labyrinth layer displayed decreased branching morphogenesis of endothelial cells, with electron microscopy evidence of attenuated trophoblast layers. The maternal decidual arteries showed increased wall-to-lumen ratios with persistence of actin-positive smooth muscle cells. These changes translated into dramatically increased vascular resistance in the uterine arteries, as measured by pulse-wave Doppler. Collectively, these results support the hypothesis that defects at the maternal-fetal interface are primary causal events in preeclampsia, and further suggest the BPH/5 model is important for investigations of the underlying pathogenic mechanisms in preeclampsia.

Role of decidual natural killer cells, interleukin-15, and interferon-γ in placental development and preeclampsia

“…These mice spontaneously develop the maternal signs of preeclampsia, including hypertension and proteinuria, as well as similar placental defects observed in human preeclamptic placentae such as inadequate remodeling of spiral arteries (6,8). We found dNK cell mRNA expression in BPH/5 implantation sites was similar to C57Bl/6 controls at e4.5 but dramatically reduced at e5.5.…”

REVIEW ARTICLE: Uterine NK Cells, Spiral Artery Modification and the Regulation of Blood Pressure During Mouse Pregnancy

“…In comparison to controls, pregnant BPH ⁄ 5 mice had equivalent uNK cell numbers but poor SA remodeling. 17 Their placentas were significantly smaller at mid-gestation (i.e. placental insufficiency) but normalized by term.…”

“…This thinking logically leads to the question of whether uNK cells contribute to regulation of MAP. [16][17][18] The principal regulator of hemodynamic function is the renal renin-angiotensin-aldosterone-system (RAS; Fig. 1).…”

Chronic Tempol Prevents Hypertension, Proteinuria, and Poor Feto-Placental Outcomes in BPH/5 Mouse Model of Preeclampsia

“…8 In addition to developing late gestational hypertension and proteinuria, BPH/5 mice also exhibit poor placental development before the onset of maternal symptoms, supporting a causative role for the placenta in this model. 9 Using this model, we tested the hypothesis that an early increase in placental oxidative stress, before the onset of maternal symptoms, plays a central role in placental dysfunction and maternal disease, and that antioxidant treatment would interrupt the disease process. We tested this hypothesis by evaluating placental ROS levels, antioxidant enzyme expression, and by using chronic antioxidant therapy using the superoxide dismutase (SOD) mimetic Tempol throughout gestation.…”