Article Text

PDF
167 TRPV4; a Potential New Target to Increase Placental Blood Flow in Fetal Growth Restricted Pregnancies?
  1. Katherine Lattey1,
  2. Helen Bischof1,
  3. Christina Haywood1,
  4. Paul Brownbill1,
  5. Sarah Jones2
  1. 1University of Manchester
  2. 2Manchester Metropolitan University

Abstract

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.

  • endothelium
  • TRPV4
  • vasodilatation

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.