Preeclampsia-Like Symptoms Induced in Mice by Fetoplacental Expression of STOX1 Are Reversed by Aspirin Treatment

Abstract

Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1, encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1. Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

“…In agreement with the implication of STOX1 in pre-eclampsia, overexpression of STOX1 was observed in early placental biopsies in gestations, eventually progressing to pre-eclampsia [GSE12767 in Founds et al (20)]. Furthermore, we induced pre-eclampsialike symptoms in two independent mouse strains overexpressing STOX1 (TgSTOX13 and TgSTOX42) (18). In the present study, we focused on the strain harboring the most severe phenotype, TgSTOX42.…”

“…RNA was extracted from placentas in TriZolÔ following classical protocols at 16.5 dpc from three different mice of each group as previously described (18). Quality control of the RNA, preparation of the probes, and hybridization on Nimblegen Mouse Expression Arrays MM8 were performed at the genom'IC platform (Cochin Institute, Paris, France) according to standard protocols.…”

“…Slides were incubated in blocking buffer (5% bovine serum albumin [BSA] in phosphate-buffered saline [PBS]) overnight at 4°C, then with the primary antibody for 1 h at room temperature (RT), and, finally, with the secondary antibody and 10 lg/ml of Hoechst 33342 for 1 h at RT. Atto488-conjugated anti-TOM22, anti-MAP1LC3B, and Immunohistochemistry of placentas was performed on WT or transgenic placentas (expressing the human STOX1 under the control of the cytomegalovirus promoter) (18). Mice were sacrificed near the end of gestation (E16.5).…”

“…Overexpression of the storkhead box 1 (STOX1) transcription factor (71) induces transcriptome alteration, mimicking pre-eclampsia in choriocarcinoma JEG-3 cells, used as proxies for trophoblast cells (56), and induces a preeclampsia-like syndrome in vivo in a transgenic mouse model (18). Major transcriptome alterations in cells overexpressing STOX1 involve several cellular pathways, among which the mitochondrial function is highly represented (56).…”

Maternal Plasma Bisulfite DNA Sequencing: Tomorrow Starts Today

“…This approach can be used to monitor both normal and abnormal changes in CpG profiles as a function of gestational age, differentiation stage, genetic variation, and/or pregnancy complications with a placental origin or such disorders as preeclampsia, HELLP 3 (hemolysis, increased liver enzymes and low platelets) syndrome, and intrauterine growth restriction. For example, the STOX1 (storkhead box 1) gene, which is associated with the familial form of preeclampsia in the Netherlands (and experimentally confirmed in a transgenic mouse model), is mainly expressed by subtypes of trophoblast cells that contribute little, if anything, to the maternal plasma RNA pool (3,4 ). This low level of expression prevents or complicates STOX1 RNA profiling if one wants to assess the risk of women carrying the susceptibility allele.…”