Curing Preeclampsia induced by STOX1A expression in Mouse Placentas by Dietary Tetrahydrobiopterin Treatment
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ABSTRACT: STOX1A overexpression in mice placenta triggers a preeclamptic phenotype in the mothers, with hypertension, proteinuria and kidney alterations (Doridot et al, Hypertension, 2013), this being connected with NO depletion and increase of nutrosative stress (Doridot et al, Antiox Redox Signal, 2014). Tetrahydrobiopterin (BH4) is a cofactor essential for NO production. We treated preeclamptic mice with this drug, and analyzed placental gene expression in four groups (Control mice, Control mice with BH4, Preeclamptic mice and preeclamptic mice with BH4).
Project description:Long-term consequences of preeclampsia were studied by high-throughput approaches (Transcriptomics, Luminex cytokine profile) in mice 8 months after the disease in the heart, in the endothelial cells and in the plasma. In the heart we found a persisting ventricular hypertrophy with an altered histology and an abnormal ultrasound Doppler profile under effort simulation by dobutamine injection. The transcriptomic profile of the endothelium revealed a deregulation for 1149 genes (327 down-regulated and 822 up-regulated, with a threshold of 1.5, p<0.05). The up-regulated genes could be grouped consistently in gene pathways and gene ontology terms mainly focused on Inflammation and Stress sensu lato. A cytokine profile of the mouse serum was carried out. Using a combination of 8 cytokines (Cxcl13, Cxcl16, Cxcl11, Il-16, Il-10, Il-2, Il-4 and Ccl1) in a Discriminant Analysis, we were able to separate unambiguously the mice having had a preeclamptic pregnancy from the controls. Seven out of eight of these cytokines (with the exception of Il-16) varied in the same direction in the endothelium and in the plasma. In sum, our study shows that preeclampsia alone is able to trigger considerable long-term consequences, and suggests that specific cytokines could help to improve the follow-up of patients long after a preeclamptic pregnancy.
Project description:Aspirin is currently the only drug used in preeclampsia, a major hypertensive disorder of pregnancy. The counselled doses are low (75-150 mg/day), and the actual effects of aspirin are not well understood, especially in the target organ, the placenta.This is the aim of the present study.
Project description:STOX1B, the short protein-coding isoform of STOX1 (227 amino acids), has been shown to present opposite effects than the one of STOX1B in trophoblast cell models. Here, we investigate the overexpression of STOX1B in vivo in the mouse placenta. The changes accompany maternal effects on blood pressure and proteinuria reminiscent of preeclampsia, and effects of Intra Uterine Growth Restriction upon the foetuses.
Project description:Long-term consequences of preeclampsia were studied by high-throughput approaches (Transcriptomics, Luminex cytokine profile) in mice 8 months after the disease in the heart, in the endothelial cells and in the plasma. In the heart we found a persisting ventricular hypertrophy with an altered histology and an abnormal ultrasound Doppler profile under effort simulation by dobutamine injection. The transcriptomic profile of the endothelium revealed a deregulation for 1149 genes (327 down-regulated and 822 up-regulated, with a threshold of 1.5, p<0.05). The up-regulated genes could be grouped consistently in gene pathways and gene ontology terms mainly focused on Inflammation and Stress sensu lato. A cytokine profile of the mouse serum was carried out. Using a combination of 8 cytokines (Cxcl13, Cxcl16, Cxcl11, Il-16, Il-10, Il-2, Il-4 and Ccl1) in a Discriminant Analysis, we were able to separate unambiguously the mice having had a preeclamptic pregnancy from the controls. Seven out of eight of these cytokines (with the exception of Il-16) varied in the same direction in the endothelium and in the plasma. In sum, our study shows that preeclampsia alone is able to trigger considerable long-term consequences, and suggests that specific cytokines could help to improve the follow-up of patients long after a preeclamptic pregnancy.
Project description:Placentas from preeclamptic pregnancies, pregnancies with Intra-uterine Growth restriction, control pregnancies from two Cohorts (Paris, Cochin Hospital and Angers Hospital) were hybridized to ClariomD microarrays and analyzed at the exon level to identify and evaluate putative anomalies in alternative splicing in human placentas.
Project description:Two pools of three placentas from transgenic mice of the TG13 strain and WT mice were hybridized on Nimblegen Arrays. TG13 mice overexpress the gene STOX1 and have the symptoms of severe preeclamsia. Total RNA was used
Project description:Trophoblast fusion is a central step in placental physiology. This mechanisms can be studied in the BeWO cell model that fuse following forskolin treatment that activates the c-AMP cascade.
Project description:The purpose of this study was to perform a comprehensive analysis of gene expression profile in placentas from preeclamptic pregnancies vs normal placentas.
Project description:Three variants of STOX1 (Y153H, T188N, and R364X) were associated to diseases of pregnancy (preeclampsia and HELLP syndrome). Here we analyze the expression profile of these mutations (6 independent clones) starting from two independent Knocked-Out cell lines (KO5 and KO21).
Project description:R3 IRCS have a 6 Mb fragment of mouse chromosome 1 originating from Mus spretus; they display a increase rate of embryonic mortality Eight samples corresponding to two pools of three placentas, three uterus for the two strains (B6 and R3 IRCS) were hybridized on a four-quadrant Nimblegen expression array (two tissues x two types of mice x 2 duplicates)