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

Departments of Obstetrics and Gynecology,⁴ Anatomy and Cell Biology⁵ Pathology,⁶ Internal Medicine and Veterans Affairs,⁷ and The Cardiovascular Center,⁸ Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242

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.

decidua, gene regulation, placenta, pregnancy, trophoblast

³These authors contributed equally to this work.

¹Supported by the American Heart Association (0540114N to R.L.D.), a predoctoral fellowship from the American Heart Association (0510021Z to D.S.H.), and a dissertation fellowship from the Woodrow Wilson National Fellowship Foundation/Johnson & Johnson (to D.S.H.).

Correspondence: ² Robin L. Davisson, Department of Biomedical Sciences, T9-014C Veterinary Research Tower, Cornell University, Ithaca, NY 14853-6401. FAX: 607 253 3378; e-mail: robin.davisson{at}cornell.edu