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Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia
Yan Zhou, … , Michael T. McMaster, Susan J. Fisher
Yan Zhou, … , Michael T. McMaster, Susan J. Fisher
Published June 24, 2013
Citation Information: J Clin Invest. 2013;123(7):2862-2872. https://doi.org/10.1172/JCI66966.
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Research Article

Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia

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Abstract

During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4%–8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) and, in some patients, fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously, we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, we cultured CTBs isolated from PE and control placentas for 48 hours, enabling differentiation and invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation, including upregulation of SEMA3B, which resolved in culture. The addition of SEMA3B to normal CTBs inhibited invasion and recreated aspects of the PE phenotype. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression; the autocrine actions of the upregulated molecules (including SEMA3B) impair CTB differentiation, invasion and signaling; and patient-specific factors determine the signs.

Authors

Yan Zhou, Matthew J. Gormley, Nathan M. Hunkapiller, Mirhan Kapidzic, Yana Stolyarov, Victoria Feng, Masakazu Nishida, Penelope M. Drake, Katherine Bianco, Fei Wang, Michael T. McMaster, Susan J. Fisher

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Figure 4

Exogenous SEMA3B mimicked the effects of sPE on CTBs and endothelial cells and inhibited angiogenesis.

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Exogenous SEMA3B mimicked the effects of sPE on CTBs and endothelial cel...
(A) The addition of anti-VEGF or SEMA3B protein significantly inhibited CTB invasion as compared with the addition of a control protein, CD6-Fc. The removal of both ligands (anti–VEGF/NRP1-Fc and anti–VEGF/NRP-2–Fc) restored invasion to control levels. (B) The variables tested in A had the opposite effects on CTB apoptosis, suggesting that increased programmed cell death contributed to decreased invasion. (C) Exogenous VEGF stimulated the migration of UtMVECs, which was inhibited by SEMA3B. (D) The results in C were quantified relative to the addition of CD6-Fc. (E) In UtMVECs, VEGF promoted survival and SEMA3B increased apoptosis relative to control levels. (F) In the chick chorioallantoic membrane angiogenesis assay, VEGF promoted angiogenesis by approximately 3 fold and SEMA3B inhibited this process approximately 5 fold relative to the effects of CD6-Fc. Arrows mark the edge of the filter paper used to apply the protein. The area of the CAM beneath the filter paper is shown in the bottom row. Scale bar: 200 μm (top row); 100 μm (bottom row). n = 6 replicates (A–D); n = 3 replicates (E and F). Mean ± SEM; 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.
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