Mitochondrial-Targeted Antioxidant Attenuates Preeclampsia-Like Phenotypes Induced by Syncytiotrophoblast-Specific Gαq Signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA915630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22890200_1.fastq.gz | Fastqsanger.gz | |||
| SRR22890200_2.fastq.gz | Fastqsanger.gz | |||
| SRR22890201_1.fastq.gz | Fastqsanger.gz | |||
| SRR22890201_2.fastq.gz | Fastqsanger.gz | |||
| SRR22890202_1.fastq.gz | Fastqsanger.gz |
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Project description:This experiment explored the placental transcriptomic effects of syncytiotrophoblast-specific Gαq signaling at gestational day 14.5 in mice and assessed whether these responses were altered upon administration of a mitochondrial-targeted antioxidant.
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Project description:Syncytiotrophoblast stress is theorized to drive development of preeclampsia, but its molecular causes and consequences remain largely undefined. Multiple hormones implicated in preeclampsia signal via the Gαq cascade, leading to the hypothesis that excess Gαq signaling within the syncytiotrophoblast may contribute. First, we present data supporting increased Gαq signaling and antioxidant responses within villous and syncytiotrophoblast samples of human preeclamptic placenta. Second, Gαq was activated in mouse placenta using Cre-lox and DREADD methodologies. Syncytiotrophoblast-restricted Gαq activation caused hypertension, kidney damage, proteinuria, elevated circulating proinflammatory factors, decreased placental vascularization, diminished spiral artery diameter, and augmented responses to mitochondrial-derived superoxide. Administration of the mitochondrial-targeted antioxidant Mitoquinone attenuated maternal proteinuria, lowered circulating inflammatory and anti-angiogenic mediators, and maintained placental vascularization. These data demonstrate a causal relationship between syncytiotrophoblast stress and the development of preeclampsia and identify elevated Gαq signaling and mitochondrial reactive oxygen species as a cause of this stress.
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Project description:The glycosylphosphatidylinositol (GPI) biosynthetic pathway in the endoplasmic reticulum (ER) is crucial for generating GPI-anchored proteins (GPI-APs), which are translocated to the cell surface and play a vital role in cell signaling and adhesion. This study focuses on two integral components of the GPI pathway, the PIGL and PIGF proteins, and their significance in trophoblast biology. We show that GPI pathway mutations impact on placental development impairing the development of the syncytiotrophoblast (SynT), and especially the SynT-II layer, which is essential for the establishment of the definitive nutrient exchange area within the placental labyrinth. CRISPR/Cas9 knockout of Pigl and Pigf in mouse trophoblast stem cells (mTSC) confirms the role of these GPI enzymes in syncytiotrophoblast differentiation. Mechanistically, impaired GPI-AP generation induces an excessive unfolded protein response (UPR) in the ER in mTSCs growing in stem cell conditions, akin to what is observed in human preeclampsia. Remarkably, the transcriptomic profile of Pigl- and Pigf-deficient cells separates human patient placental samples into preeclampsia and control groups suggesting an involvement of Pigl and Pigf in establishing a preeclamptic gene signature. Upon differentiation, the impairment of the GPI pathway hinders the induction of WNT signaling for early SynT-II development. Our study unveils the pivotal role of GPI biosynthesis in early placentation and uncovers a new preeclampsia gene expression profile associated with mutations in the GPI biosynthesis pathway, providing novel molecular insights into placental development with implications for enhanced patient stratification and timely interventions.
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Project description:Preeclampsia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preeclampsia and pharmacological elevation of IL11 in pregnant mice causes the development of preeclampsia-like features (hypertension and proteinuria), however, the mechanism by which IL11 drives preeclampsia-like features is unknown. Using Next-generation sequencing we demonstrate that treatment with PEGylated IL11 (PEGIL11) inhibited placental expression of markers of spongiotrophoblast and syncytiotrophoblast linages and increased placental cathepsin production in wild-type and Asc-/- mice. Function studies showed that IL11 acts via Asc inflammasomes to induce tissue fibrosis and preeclampsia in mice. This study has far-reaching implications on our understanding of the underlying etiology of preeclampsia and the mechanism by which IL11 causes inflammation and fibrosis in many tissues and disease states.
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Project description:CO2-induced vasoreactivity is an important mechanism to remove CO2 from the brain. Our previous work has shown that in brain endothelial cells Gαq and Gα11, that can replace each other and induce a common intracellular pathway, are required for normal vascular reactivity to CO2 stimulation. Additionally, we found different effects on vascular diameter dependent on the brain area. In the cortex, vessel dilate as response to CO2 stimulation, in the retrotrapezoid nucleus (RTN) of the brainstem, vessels constrict upon CO2 stimulation. To examine the potential basis for the opposing effects of CO2 on the vascular reactivity in brainstem compared to other brain areas, we prepared cortical and brainstem vessel fragments of control and Gαq/11beKO mice and performed microarrays to determine mRNA expression.
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2025-05-07 | PXD052342 | Pride
Project description:Background: Long non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. They are aberrantly expressed in many types of diseases. We want to study the lncRNAs profiles in preeclampsia. Preeclampsia has been observed in patients with molar pregnancy where a fetus is absent demonstrating that the placenta is sufficient to cause the condition. So we analyze the lncRNAs profiles in preeclampsia placentas. In this study, we described the lncRNAs profiles in 6 preeclampsia placentas (T) and 5 matched normal pregnancy placentas (N) tissues by microarray. Methodology/Principal Findings: With abundant and varied probes accounting 33,045 LncRNAs in our microarray, the number of lncRNAs that expressed at a certain level could be detected is 28,443. From the data we found there were 738 lncRNAs that differentially expressed (M-bM-^IM-%1.5 fold-change) among preeclampsia placentas compared with matched controls. Up to 18,063 coding transcripts could be detected in placenta samples through 30,215 coding transcripts probes. Coding-non-coding gene co-expression networks (CNC network) were constructed based on the correlation analysis between the differential expressed lncRNAs and mRNAs. According to the GO-Pathway analysis of differential expressed lncRNAs/mRNAs, we choose three lncRNAs to analyze the relationship between lncRNAs and preeclampsia. LOC391533, LOC284100, CEACAMP8 were evaluated by qPCR in 40 of preeclampsia placentas and 40 of controls. The results showed three lncRNAs were aberrantly expressed in preeclampsia placentas compared with controls. Conclusions/Significance: Our study is the first one to determine genome-wide lncRNAs expression patterns in preeclampsia placenta by microarray. The results displayed that clusters of lncRNAs were aberrantly expressed in preeclampsia placenta compared with controls, which revealed that lncRNAs differentially expressed in preeclampsia placenta may exert a partial or key role in preeclampsia development. Misregulation of LOC391533, LOC284100, CEACAMP8 might be associated with preeclampsia. Taken together, this study may provide potential targets for future treatment of preeclampsia and novel insights into preeclampsia biology. LncRNAs/mRNAs profiles in 6 preeclampsia placentas and 5 matched normal pregnancy placentas tissues by microarray using Arraystar v2.0.
2013-09-12 | E-GEOD-50783 | biostudies-arrayexpress
Project description:Preeclampsia is a severe placenta-related pregnancy disorder that is generally divided into two subtypes named early-onset preeclampsia (onset <34 weeks of gestation), and lateonset preeclampsia (onset ≥34 weeks of gestation), with distinct pathophysiological origins. Both forms of preeclampsia have been associated with maternal systemic inflammation. However, alterations in the placental immune system have been less well characterized. Here, we studied immunological alterations in early- and late-onset preeclampsia placentas using a targeted expression profile approach. RNA was extracted from snap-frozen placenta samples (healthy n=13, early-onset preeclampsia n=13, and late-onset preeclampsia n=6). The expression of 730 immune-related genes from the Pan Cancer Immune Profiling Panel was measured, and the data were analyzed Q10 in the advanced analysis module of nSolver software (NanoString Technology). The results showed that early-onset preeclampsia placentas displayed reduced expression of complement, and toll-like receptor (TLR) associated genes, specifically TLR1 and TLR4. Mast cells and M2 macrophages were also decreased in early-onset preeclampsia compared to healthy pl acentas. The findings were confirmed by an immunohistochemistry approach using 20 healthy, 19 early-onset preeclampsia, and 10 late-onset preeclampsia placentas. We conclude that the placental innate immune system is altered in early-onset preeclampsia compared to uncomplicated pregnancies. The absence of these alterations in late-onset preeclampsia placentas indicates dissimilar immunological profiles. The study revealed distinct pathophysiological processes in earlyonset and late-onset preeclampsia placentas and imply that a tailored treatment to each subtype is desirable.
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Project description:Background. Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the mechanism of this effect is not clear. Objectives. Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq. Methods. Gαq and wild-type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow). Results. From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis – all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by 31P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU. Conclusions. The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, thereby leading to increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.
2025-04-30 | GSE276289 | GEO