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.