Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1

Abstract

Introduction Elevated circulating soluble FLT1 (sFLT1) levels in preeclampsia may play a role in its development. Aspirin is recommended for prevention of preeclampsia. We hypothesized that aspirin may inhibit the production of sFlt1. Methods Placentas from women with and without preeclampsia were collected. Primary cytotrophoblasts (CTBs) were cultured from normal placentas and treated with aspirin, sc-560, a COX1 inhibitor or celecoxib, a COX-2 inhibitor. The expression of sFLT1, FLT1, COX1, COX2 was studied. The effect of aspirin on sFlt1 expression was also studied in HEK293 cells and in HTR-8/SVNeo cells. Results The expression of sFLT1 was increased in preeclamptic placentas compared to control placentas and the expression and release of sFLT1 increased in CTBs exposed to 2% O2 compared to controls. Aspirin at 3 and 12 mM concentration reduced the expression and release of sFLT1 in CTBs. Aspirin also inhibited sFlt1 expression from HTR-8/SVNeo and HEK293 cells. Sc-560, but not celecoxib, reduced sFLT1 expression and release from CTBs. Aspirin and sc-560 also reduced hypoxia-induced FLT1 mRNA expression and inhibited COX1 mRNA in CTBs. Discussion This study confirms that sFLT1 expression is increased in preeclamptic placentas and in CTBs exposed to hypoxia. Aspirin inhibits the production sFLT1 in CTBs and in HTR-8/SVNeo. Sc-560 recapitulated the effects of aspirin on sFLT1 expression and release in CTBs suggesting that the aspirin effect may be mediated via inhibition of COX1. The study increases our understanding of the mechanisms regulating sFlt1 expression and provides a plausible explanation for the effect of aspirin to prevent preeclampsia.

Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study

“…31-33, 36 Aspirin, recommended for SLE pregnancies and studied in PE prevention trials, may decrease sFlt1 production by trophoblasts. 34, 37, 38 Importantly, neither heparin nor aspirin exposure limited the strong prognostic value of angiogenic factors in predicting severe APO in this study.…”

“…Heparin and low dose aspirin are standard treatments for pregnant women with antiphospholipid syndrome (APS), aspirin alone for those with only APL 31 ; both may alter angiogenic factor levels. 32-34 Patients receiving heparin had significantly higher sFlt1 levels, sFlt1/PlGF ratios, and lower PlGF levels at 12-15 weeks, compared to untreated women; sEng levels were not significantly different between these groups (Table B). Treatment with heparin was associated with a higher risk of severe APO in bivariate analyses but not after adjusting for other covariates.…”

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study

“…If replicated in longitudinal studies, these data may provide a basis for targeted interventions to prevent long-term complication of schizophrenia. Current therapeutic avenues that decrease the expression of sFlt-1 [antipsychotics (Buckley et al , 2007), sulfasalazine (Brownfoot et al , 2015b), aspirin (Li et al , 2015), statins (Brownfoot et al , 2015a), proton pump inhibitors (Onda et al , 2015), and choline (Jiang et al , 2013)] and modulate autoimmune disorders are already in existence.…”

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

“…(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. However, when Kaandorp et al 's study (56) is excluded, the effect of aspirin on the rate of any hypertensive disorder of pregnancy becomes significant (Table 3).…”