Long-term cardiovascular disorders in the STOX1 mouse model of preeclampsia

Miralles, Francisco; Collinot, Hélène; Boumerdassi, Yasmine; Ducat, Aurélien; Duché, A; Renault, Gilles; Marchiol, Carmen; Lagoutte, Isabelle; Bertholle, Céline; Andrieu, Muriel; Jacques, Sébastien; Méhats, Céline; Vaiman, Daniel

doi:10.1038/s41598-019-48427-3

Cited by 29 publications

(22 citation statements)

References 66 publications

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“…The implications of QKI5‐mediated effects in vivo during the progression of PE was studied using an adoptive transfer mouse model where received cells overexpressing QKI5. This model was chosen over the STOX‐1 model that recapitulates early PE maternal syndrome and other available PE models as it proved relevant to study both placental pathology and symptoms related to PE such as rise in blood pressure and increased urine/creatine levels 43,44 . Placental tissues harvested towards the end of gestation revealed a significant increase in cell proliferation in the QKI5 treatment group.…”

Section: Discussionmentioning

confidence: 99%

NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

Yang

Chen

et al. 2021

J Cellular Molecular Medi

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Preeclampsia (PE) is characterized by placental ischemia and hypoxia, resulting in abnormal casting of the uterine spiral artery, which is mainly caused by insufficient trophoblastic cell infiltration. A reduction in levels of growth factor‐based signalling via Neuropilin‐1 (NRP1) has been shown to contribute to dysfunctional trophoblast development. In this study, we showed that the RNA‐binding protein, QKI5, regulated NRP1 expression and significantly improved trophoblast proliferation in vitro and in vivo. QKI5 and NRP1 expressions were significantly reduced in human PE placentas and in trophoblasts during hypoxia. Overexpression of these factors significantly improved cell proliferation and migration in vitro, in contrast to a decrease upon siRNA knockdown of QKI5 and NRP1 in HTR‐8/SVneo cells. Using RIP and RNA pull‐down assays, we further showed that QKI5 directly interacted with the 3'‐UTR region of NRP1, to mediate cell proliferation and migration via matrix metalloprotease‐9. Further, similar to NRP1, QKI5 also targets matrix metalloproteinase 9 (MMP9) involved in secretion of growth factors and its effects can be counteracted by NRP1 overexpression. In vivo studies using a PE mouse model revealed that QKI5 overexpression alleviated PE‐related symptoms such as elevated blood pressure and proteinuria. Taken together, we found that QKI5 was a novel regulator, of VEGF‐R/NRP1 signalling pathway functioning in trophoblast proliferation and migration, resulting in major contributors to the pathogenesis of PE. While careful evaluation of the broad implications of QKI5 expression is still necessary, this study identified QKI5 as a promising target for treatment strategies in acute PE patients.

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Section: Discussionmentioning

confidence: 99%

NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

Yang

Chen

et al. 2021

J Cellular Molecular Medi

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“…In our study, we chose time points up to 10 wk postpartum, modelling the human equivalent of ∼1, 2, 4, and 9.5 yr post-delivery. Expanding the study to include later time points (beyond 10 wk post-delivery) may have uncovered further cardiovascular changes, as another model has shown ( 94 ). However, the time points used in this study were chosen to reflect the clinical phenomena, examining earlier time points akin to human clinical observations, as individuals demonstrate impaired cardiovascular function soon after a pregnancy complicated by preeclampsia ( 13 , 48 ).…”

Section: Discussionmentioning

confidence: 99%

The L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health

et al. 2022

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Preeclampsia affects ∼2–8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney Mmp9:Timp1 and heart Tnf mRNA expression, indicating increased inflammation. These findings suggest that though administration of L-NAME in mice certainly models key characteristics of preeclampsia during pregnancy, it does not appear to model the adverse increase in cardiovascular disease risk seen in individuals after preeclampsia.

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“…The severity of the transgenic phenotype is illustrated by the initiation of hypertension in the preimplantation period, blood pressure increases exceeding 60 mmHg, and a 20%–30% reduction in litter size ( 25 ). Subsequent studies of the transgenic mouse showed fetal growth restriction ( 49 ), cardiovascular dysfunction ( 24 ), and postpartum cardiac alterations ( 50 ), indicating that this mouse may be a useful model for severe preeclampsia. In contrast, the Stox1-KO phenotype was driven by endogenous upregulation of renin, which would not be expected to have as striking a phenotype because of the presence of intact blood pressure and RAS regulatory mechanisms, and is more consistent with human gestational hypertension.…”

Section: Discussionmentioning

confidence: 99%

STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects

Parchem¹,

Kanasaki²,

Lee³

et al. 2021

JCI Insight

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The pathogenesis of preeclampsia and other hypertensive disorders of pregnancy remains poorly defined despite the substantial burden of maternal and neonatal morbidity associated with these conditions. In particular, the role of genetic variants as determinants of disease susceptibility is understudied. Storkhead-box protein 1 ( STOX1 ) was first identified as a preeclampsia risk gene through family-based genetic linkage studies in which loss-of-function variants were proposed to underlie increased preeclampsia susceptibility. We generated a genetic Stox1 loss-of-function mouse model (Stox1 KO) to evaluate whether STOX1 regulates blood pressure in pregnancy. Pregnant Stox1-KO mice developed gestational hypertension evidenced by a significant increase in blood pressure compared with WT by E17.5. While severe renal, placental, or fetal growth abnormalities were not observed, the Stox1-KO phenotype was associated with placental vascular and extracellular matrix abnormalities. Mechanistically, we found that gestational hypertension in Stox1-KO mice resulted from activation of the uteroplacental renin-angiotensin system. This mechanism was supported by showing that treatment of pregnant Stox1-KO mice with an angiotensin II receptor blocker rescued the phenotype. Our study demonstrates the utility of genetic mouse models for uncovering links between genetic variants and effector pathways implicated in the pathogenesis of hypertensive disorders of pregnancy.

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Long-term cardiovascular disorders in the STOX1 mouse model of preeclampsia

Cited by 29 publications

References 66 publications

NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

The L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health

STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects

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