In vitro Examination of Piezo1-TRPV4 Dynamics: Implications for Placental Endothelial Function in Normal and Preeclamptic Pregnancies

Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE) impacting offspring health. The ion channels Piezo1 and TRPV4 are co-regulated mechanosensors in ECs. Here we show functional co-expression of both channels in feto-placental ECs (fpECs) and that calcium influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs, also with a stronger effect in EPE fpECs. This implies altered Piezo1-TRPV4 co-regulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA-Seq. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future. Overall design: Placentae were obtained immediately after delivery of singleton pregnancies at the Department of Obstetrics and Gynecology, Medical University of Graz, Austria. Collection and sample processing were approved by the ethics committee of the Medical University of Graz, Austria (29-319 ex 16/17) and voluntary detailed consent was taken from all study participants. Exclusion criteria were maternal systemic disease, other pregnancy complications, nicotine use during pregnancy, and a body mass index of <18 or >27 before pregnancy. The control samples were divided into two control groups: those delivered at =38 weeks of gestation called term controls (TC) and those delivered at <38 weeks of gestation called early controls (EC), the latter being age-matched to the early-onset PE group (EPE). EPE was diagnosed by a qualified clinician according to ACOG guidelines (new–onset hypertension with a blood pressure of =140/90 mmHg plus organ manifestation with onset of maternal symptoms <34 weeks of gestation). Clinical characteristics can be found in Table 1 of the repsective publication. For the study gene expression was compared between the groups.