Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia

Souders, Colby A.; Maynard, Sharon E.; Yan, Jing; Wang, Yang; Boatright, Naomi K.; Sedan, Jessica; Balyozian, David; Cheslock, Peter S.; Molrine, Deborah C.; Simas, Tiffany A. Moore

doi:10.3390/ijms160612436

Cited by 20 publications

(14 citation statements)

References 44 publications

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“…Three sFLT1 mRNA isoforms, sFLT1-i13 short, sFLT1-i13 long , and sFLT1-e15a predominantly contribute to the expression of sFLT1 protein, that circulates at high levels in patients with preterm PE 4, 28–30 . Thus all three isoforms need to be targeted to productively decrease the levels of circulating sFLT1 protein across the spectrum of PE patients.…”

Section: Resultsmentioning

confidence: 99%

RNAi modulation of placental sFLT1 for the treatment of preeclampsia

et al. 2018

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Preeclampsia (PE) is a placentally-induced hypertensive disorder of pregnancy that is associated with significant morbidity and mortality to mothers and fetuses. Clinical manifestations of preterm PE result from excess circulating soluble vascular endothelial growth factor receptor FLT1 (sFLT1 or sVEGFR1) of placental origin. Here we identify short interfering RNAs (siRNAs) that selectively silence the three sFLT1 mRNA isoforms primarily responsible for placental overexpression of sFLT1. Full chemical stabilization in the context of hydrophobic modifications enables productive siRNA accumulation in the placenta (up to 7% of injected dose) and reduces circulating sFLT1 in pregnant mice (up to 50%). In a baboon PE model, single dose of siRNAs suppressed sFLT1 overexpression and clinical signs of PE. Our results demonstrate RNAi-based extra-hepatic modulation of gene expression with non-formulated siRNAs in non-human primates and establish a path toward a new treatment paradigm for patients with preterm PE.

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Section: Resultsmentioning

confidence: 99%

RNAi modulation of placental sFLT1 for the treatment of preeclampsia

et al. 2018

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“…A number of splice variants of sFlt-1 have been identified 8 , 10 . In particular, the expression of the sFlt-1 i13 variant is widely distributed in most human tissues and it is significantly elevated in preeclamptic women (> 34 weeks) 11 while the sFLT-1 e15a variant, highly expressed in the placenta, is significantly upregulated in severe preeclampsia 12 .…”

Section: Introductionmentioning

confidence: 99%

Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells

Sanchez-Aranguren

Ahmad

Dias

et al. 2020

Sci Rep

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Endothelial dysfunction is a hallmark of preeclampsia, a life-threatening complication of pregnancy characterised by hypertension and elevated soluble Fms-Like Tyrosine Kinase-1 (sFlt-1). Dysregulation of hydrogen sulfide (H2S) by inhibition of cystathionine γ-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE/H2S pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE/H2S pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted H2S donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial H2S metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting H2S to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.

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“…The increase of FLT1 protein level is an important risk factor leading to impaired placental angiogenesis [ 26 ]. In fact, the expression level of FLT1 in serum of the large number of women with PE were significantly elevated [ 27 – 31 ], while after 48 h of delivery, the level of FLT1 in serum decreased dramatically [ 32 , 33 ]. Patients with GDM tend to develop dysfunction of vascular endothelial cells and atherosclerosis, leading to PE [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Screening of differentially expressed proteins from syncytiotrophoblast for severe early-onset preeclampsia in women with gestational diabetes mellitus using tandem mass tag quantitative proteomics

Sun

et al. 2018

BMC Pregnancy Childbirth

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BackgroundPrevious studies have revealed that women with gestational diabetes mellitus (GDM) have an increased risk of developing preeclampsia (PE). The possible reason is the abnormal lipid metabolism caused by GDM that leads to dysfunction of vascular endothelial cells and atherosclerosis, resulting in the onset of PE. However, studies focusing on the pathogenesis of PE in syncytiotrophoblast of GDM patients are lacking. This study aimed to compare differentially expressed proteins from syncytiotrophoblast between women with GDM and women with GDM with subsequently developed PE.MethodsSyncytiotrophoblast samples were obtained from pregnant women immediately after delivery. To explore the protein expression changes of syncytiotrophoblast that might explain the pathogenesis of PE in women with GDM, quantitative proteomics was performed using tandem mass tag (TMT) isobaric tags and liquid chromatography-tandem mass spectrometry. Bioinformatics analysis was performed to enrich the biological processes that these differentially expressed proteins were involved in.ResultsA total of 28,234 unique peptides and 4140 proteins were identified in all samples. Among them, 23 differentially expressed proteins were identified between patients with GDM and patients with GDM with subsequently developed PE. Therein, 11 proteins were upregulated and 12 proteins were downregulated. Two relative proteins (FLT1 and PABPC4) were independently verified using immunoblotting analysis. Bioinformatic results indicated that the onset of PE in patients with GDM is a multifactorial disorder, involving factors such as apoptosis, transcriptional misregulation, oxidative stress, lipid metabolism, cell infiltration and migration, and angiogenesis.ConclusionThese results indicated that the inadequacy of endometrium infiltration, angiogenic disorder, and oxidative stress in syncytiotrophoblast are more likely to occur in patients with GDM and may be the potential mechanisms leading to such patients secondarily developing severe early-onset PE.

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Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia

Cited by 20 publications

References 44 publications

RNAi modulation of placental sFLT1 for the treatment of preeclampsia

RNAi modulation of placental sFLT1 for the treatment of preeclampsia

Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells

Screening of differentially expressed proteins from syncytiotrophoblast for severe early-onset preeclampsia in women with gestational diabetes mellitus using tandem mass tag quantitative proteomics

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