Preeclampsia is a serious obstetric condition affecting approximately 3-8% of pregnancies worldwide [1]. It is characterised by gestational hypertension at or after 20 weeks gestation, accompanied by one or more of uteroplacental insufficiency, proteinuria, or major organ dysfunction [2]. We still do not completely understand the pathways driving preeclampsia pathogenesis. Furthermore, there is no cure for preeclampsia and limited treatment options are available. Delivery remains the only way to stop disease progression once preeclampsia is underway. Hence, it is vital that we improve our understanding of the mechanisms driving disease pathogenesis, to identify potential targets for treatment and to enhance early diagnosis/risk stratification.

Dishevelled Associated Activator Of Morphogenesis 2 (DAAM2) is a gene known mainly for its role in the Wnt/β-catenin signalling pathway [[3], [4]]. Recent studies have discovered that DAAM2 may also have a role in fetal growth restriction and placental dysfunction. In mice, DAAM2 was described to be important in placental vascularisation and establishing the fetal-maternal blood supply [5]. In humans, our team demonstrated that DAAM2 transcripts were highly elevated in the circulation of individuals whose pregnancies were complicated by fetal growth restriction (± preeclampsia) compared to those with appropriately grown fetuses [[6], [7]]. Furthermore, we also identified that DAAM2 levels are increased in human placental tissue collected from cases of fetal growth restriction, and in whole placental tissue and cytotrophoblast cells exposed to hypoxia (as a model of placental dysfunction, a characteristic of both fetal growth restriction and preeclampsia) [7]. Additionally, we identified that suppressing cytotrophoblast DAAM2 may have cytoprotective effects, hence DAAM2 could be a target for treating placental disease [7].

However, an association of altered placental DAAM2 levels in placenta from pregnancies complicated by preeclampsia, or a correlation with the pathogenesis that drives preeclampsia - particularly regulation of the anti-angiogenic factor sFlt-1, has not previously been examined. Placental insufficiency and dysfunction are common features of both fetal growth restriction and preeclampsia. Whilst the consequences of placental insufficiency in fetal growth restriction are primarily observed in the placenta and fetus, preeclampsia is more complex, impacting both the fetal and maternal systems. Uniquely in preeclampsia, the dysfunctional placenta releases anti-angiogenic and pro-inflammatory factors into the maternal circulation that enhance widespread endothelial dysfunction, and instigate maternal disease.

Here we aimed to determine if DAAM2 plays a role in the pathogenesis associated with preeclampsia. We set out to investigate whether DAAM2 is dysregulated in placenta from cases of early-onset (preterm) preeclampsia. Given our previous findings where we demonstrated that silencing DAAM2 in cytotrophoblast reduced oxidative stress markers and increased anti-oxidant markers [7], we examined whether treatment with the proton pump inhibitors, esomeprazole, lansoprazole and rabeprazole, previously identified to enhance cytoprotective molecules and reduce sFLT-1 in the human placenta [8], altered placental DAAM2 mRNA in vitro.