Introduction Fetal growth restriction (FGR) is a pregnancy complication that predisposes to an increased risk of neonatal morbidity and mortality. A low birth weight is also associated with increased risk of cardiovascular disease and metabolic syndrome in adulthood. While the aetiology of FGR is unknown, reduced fetoplacental blood flow is thought to be a major contributing factor. Normal fetal growth requires a high-flow low-resistance fetoplacental circulation, maintained by vasodilatation. One of the most potent stimulators of vasodilatation is shear stress.

Understanding the mechanisms that regulate shear stress-mediated vasodilatation in the placenta may reveal novel therapeutic targets in pregnancies complicated by increased vascular resistance such as FGR. The aim of this study was to investigate whether the potential shear stress sensor TRPV4 was present on the fetoplacental endothelium and involved in regulating vascular tone.

Methods TRPV4 expression in placental vessels was determined using immunohistochemistry. To examine endothelial specific expression, Western blots were performed on lysates from human placental artery endothelial cells (HPAECs). TRPV4 mediated Ca²⁺responses were measured in FURA2 loaded HPAECs using a FlexStation3 and single cell Ca²⁺ imaging. Nitric oxide and PGI₂ release from HPAECs was measured following TRPV4 stimulation and placental vascular reactivity measured using wire myography.

Results Shear stress induced elevation of [Ca²⁺]_i in HPAECs was largely dependent upon Ca²⁺ influx, indicating the involvement of a Ca²⁺ permeable cation channel. TRPV4 was expressed by placental vessels and more specifically was shown to be expressed by HPAECs. Stimulation of TRPV4 (GSK1016790A 0.1–100µM) resulted in a dose-dependent transient Ca²⁺ influx in HPAECS which was abolished by EGTA (4 mM). Incubation of HPAECS with GSK1016790A (0.5 µM) induced nitric oxide and PGI₂ generation indicating that TRPV4 is capable of regulating vascular tone in the placenta. Furthermore, application of GSK1016790A (0.5 µM) to pre-constricted chorionic plate arteries stimulated a 51.9% relaxation of intact vessels and 28.2% relaxation of endothelial denuded vessels, demonstrating that TRPV4 mediates both endothelial dependent and independent vasodilatation of placental vessels.

Conclusion TRPV4 stimulates vasodilatation of placental vessels through a variety of signalling pathways and may offer a novel therapeutic target in pregnancies complicated by increased vascular resistance.