The effect of acetyl salicylic acid (Aspirin) on trophoblast-endothelial interaction in vitro

Xu, Bei; Shanmugalingam, Renuka; Chau, Katrina; Pears, Suzanne; Hennessy, Annemarie; Makris, Angela

doi:10.1016/j.jri.2017.10.044

Cited by 29 publications

(20 citation statements)

References 55 publications

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“…Therefore, we next sought to assess the effect of loss of BRD4 on sFLT1 production in trophoblast cells and HUVECs. As has previously been reported (Xu et al 2017), TNF does not increase either sFLT1 (e15a and i13 variants) mRNA expression or sFLT1 secretion in trophoblast cells (Fig. 4).…”

Section: Brd4 Inhibition Decreases Sflt1 In Primary Trophoblasts and supporting

confidence: 88%

Bromodomain protein BRD4 is increased in human placentas from women with early-onset preeclampsia

Liong¹,

Barker²,

Lappas³

2018

Reproduction

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Preeclampsia affects 5% of all pregnancies and is a serious disorder of pregnancy, characterised by high maternal blood pressure, placental hypoxia, fluid retention (oedema) and proteinuria. Women with preeclampsia are associated with exaggerated levels of pro-inflammatory cytokines, chemokines and anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFLT1). Studies in non-gestational tissues have described the bromodomain (BRD) and extraterminal family of proteins, in particular BRD4 to play a critical role in propagating inflammation and is currently a therapeutic target for treating cancer, lung inflammation and asthma. The aims of this study were to: (i) determine the effect of severe early-onset preeclampsia on placental BRD4 expression; (ii) the effect of loss of BRD4 function by siRNA-targeted knockdown or with the BRD inhibitor JQ1 in human primary trophoblast cells and human umbilical vein endothelial cells (HUVECs) on TNF-stimulated production of pro-inflammatory mediators, cell adhesion molecules and anti-angiogenic markers and (iii) the effect of BRD4 suppression on placental sFLT1 secretion under hypoxia conditions and in preeclampic placenta. BRD4 mRNA expression was significantly increased (sevenfold) in severe early-onset preeclampsia placenta. BRD4 silencing resulted in a significant reduction in TNF-induced ,, , and - mRNA expression and IL6, CXCL8, CCL2, CXCL1 and sFLT1 secretion in primary trophoblast and HUVECs. Additionally, JQ1 treatment significantly reduced placental sFLT1 secretion under hypoxic conditions and in preterm preeclamptic placenta. In conclusion, these findings suggest BRD4 may play a central role in propagating inflammation and endothelial dysfunction associated with the pathophysiology of early-onset preeclampsia.

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Section: Brd4 Inhibition Decreases Sflt1 In Primary Trophoblasts and supporting

confidence: 88%

Bromodomain protein BRD4 is increased in human placentas from women with early-onset preeclampsia

Liong¹,

Barker²,

Lappas³

2018

Reproduction

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“…(93) In addition, aspirin has been shown to improve trophoblast-endothelial cell integration in in vitro studies by inhibiting the effect of tumor necrosis factor-alpha via prostacyclin production without any effects on anti-angiogenic, invasive (matrix metalloproteinase) or endothelial activation markers. (94,95) However, in an in vivo study, aspirin has been shown to inhibit the expression of soluble fms-like tyrosine kinase (sFlt-1) in cytotrophoblast cultured cells, under a hypoxic state, from placentas of women with confirmed preeclampsia. (96) The result of the current meta-analysis indicates that the administration of low-dose aspirin at <11 weeks' gestation is associated with a nonsignificant decrease in the risk of preeclampsia, gestational hypertension, and any hypertensive disorder of pregnancy.…”

Section: Resultsmentioning

confidence: 99%

Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia?

Chaemsaithong

Cuenca-Gomez

Plana

et al. 2020

American Journal of Obstetrics and Gynecology

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Condensation: Aspirin given at <11 weeks' gestation in high risk women does not reduce the risk of preeclampsia and gestational hypertension but may reduce the risk of preterm delivery. Short title: Early aspirin administration and preeclampsia PROSPERO registration number: CRD42019125006 AJOG at a Glance: Why was this study conducted? • To perform a systematic review and meta-analysis to evaluate the effect of lowdose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. Key findings • The administration of low-dose aspirin at <11 weeks' gestation in women with a history of recurrent pregnancy loss, women who had undergone in vitro fertilization or women with thrombophilia or antiphospholipid syndrome was associated with a non-significant decrease in the risk of preeclampsia, gestational hypertension, and any hypertensive disorder of pregnancy. • Early low-dose aspirin reduced the risk of preterm delivery but had no impact on the risk of fetal growth restriction. • Except for preterm delivery and any hypertensive disorder of pregnancy, sensitivity analysis demonstrated similar observations; confirming the robustness of our analysis. What does this add to what is known? • Administration of low-dose aspirin at <11 weeks' gestation to high risk women does not reduce the risk of preeclampsia, gestational hypertension, any hypertensive disorder of pregnancy and fetal growth restriction but might reduce the risk of preterm delivery at <37 weeks of gestation. ABSTRACT OBJECTIVE DATA: Pre-conception or early administration of low-dose aspirin might improve endometrial growth, placental vascularization and organogenesis. Most studies have evaluated the potential benefit of pre-conception or early administration of low-dose aspirin in women with a history of recurrent pregnancy loss, women who have undergone in vitro fertilization or women with thrombophilia or antiphospholipid syndrome. These women are at an increased risk of placenta-associated complications of pregnancy, including preeclampsia, preterm delivery and fetal growth restriction. STUDY: We performed a systematic review and meta-analysis to evaluate the effect of low-dose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. STUDY APPRAISAL AND SYNTHESIS METHODS: We searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.Gov and the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) from 1985 to November 2018. Entry criteria were randomized controlled trials evaluating the effect of aspirin administered at <11 weeks' gestation in preventing preeclampsia and/or hypertensive disorders in pregnancy or improvi...

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“…The effect of aspirin on angiogenic factors, such as sFlt-1 and PlGF is the subject of ongoing interest and has been examined in several in vitro studies [27,28,29,30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Li et al reported that aspirin seems to be able to block the production of sFlt1 in the placenta in a dose-dependent manner, suggesting that aspirin exerts its therapeutic effects via cyclooxygenase-1 inhibition [27]. However, Xu et al demonstrated in their in vitro study that aspirin improves trophoblast cell integration by inhibiting the effect of TNF-alpha via PGI2, but without affecting VEGF, PlGF and sFlt-1 [28].…”

Section: Discussionmentioning

confidence: 99%

Effect of Low-Dose Aspirin on Soluble FMS-Like Tyrosine Kinase 1/Placental Growth Factor (sFlt-1/PlGF Ratio) in Pregnancies at High Risk for the Development of Preeclampsia

Mayer-Pickel

Kolovetsiou-Kreiner

Stern

et al. 2019

JCM

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Background: Soluble FMS-like Tyrosine Kinase 1 (sFlt-1) and placental growth factor (PlGF) have been reported to be highly predictive several weeks before the onset of preeclampsia. Objective: To investigate longitudinal changes of serum levels sFlt-1 and PlGF in pregnant women at high risk for the development of preeclampsia and to reveal an impact of aspirin on maternal serum concentrations of sFlt-1 and PlGF. Methods: This was a prospective longitudinal study in 394 women with various risk factors for the development of preeclampsia (chronic hypertension, antiphospholipid syndrome/APS or systemic lupus erythematosus/SLE, thrombophilia, women with a history of preeclampsia, pathologic first trimester screening for preeclampsia) and 68 healthy women. Serum levels of sFlt-1 and PlGF were measured prospectively at 4-week intervals (from gestational weeks 12 until postpartum). Results: The sFlt-1/PlGF ratio was significantly higher in women with an adverse obstetric outcome compared to women with a normal pregnancy, starting between 20 and 24 weeks of gestation. There was no effect of aspirin on sFlt-1/PlGF ratio in women with chronic hypertension, APS/SLE, thrombophilia and controls. The use of aspirin showed a trend towards an improvement of the sFlt-1/PlGF ratio in women with preeclampsia in a previous pregnancy and a significant effect on the sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia. Conclusions: Our findings reveal an impact of aspirin on sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia, strongly supporting its prophylactic use.

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The effect of acetyl salicylic acid (Aspirin) on trophoblast-endothelial interaction in vitro

Cited by 29 publications

References 55 publications

Bromodomain protein BRD4 is increased in human placentas from women with early-onset preeclampsia

Bromodomain protein BRD4 is increased in human placentas from women with early-onset preeclampsia

Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia?

Effect of Low-Dose Aspirin on Soluble FMS-Like Tyrosine Kinase 1/Placental Growth Factor (sFlt-1/PlGF Ratio) in Pregnancies at High Risk for the Development of Preeclampsia

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