The β-isoform of the Thromboxane A<sub>2</sub> Receptor (TPβ) in pregnancy – the missing link between oxidative stress and poor placentation — The Association Specialists
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  3. The β-isoform of the Thromboxane A2 Receptor (TPβ) in pregnancy – the missing link between oxidative stress and poor placentation

The β-isoform of the Thromboxane A2 Receptor (TPβ) in pregnancy – the missing link between oxidative stress and poor placentation (369)

Katie L Powell 1 , Veronica Stevens 1 , Dannielle Upton 1 , Ann Simpson 2 , Vitomir Tasevski 1 2 3 , Jonathan M Morris 1 , Anthony W Ashton 1
  1. Kolling Institute of Medical Research, St Leonards, NSW, Australia
  2. School of Medical and Molecular Biosciences, University of Technology (Sydney) , Ultimo, NSW, Australia
  3. Fetal Maternal Medicine, PaLMs, Pathology North, St Leonards, NSW, Australia

Background: Normal placental development is essential for successful pregnancy. Defective invasion of the uterine wall and spiral arteries by extravillous cytotrophoblasts impairs placentation, prevents establishment of adequate blood supply to the placenta in the first trimester and ultimately limits uteroplacental perfusion which can result in pre-eclampsia (PE) later in gestation. PE affects ~3-10% of pregnancies and is characterised by clinical symptoms of hypertension and proteinuria. Elevated levels of the human-specific receptor TPβ and its ligands (thromboxane A2 and isoprostanes) are readily detectable in pregnant women affected by PE; however, the role of TPβ in regulating placentation is largely unexplored.

Aim: To understand the differential regulation of trophoblast function by TPα and TPβ during placentation.

Methods: Stable ectopic expression of TPα, TPβ or TP328 (the region common to both receptors) in trophoblast cell lines (BeWo, JEG-3) was achieved using transfection and the effect of these receptors on differentiation (syncytialization), motility and proliferation was assessed.

Results: TPα expression enhanced proliferation (through enhanced expression of cyclins A/D1 and E), syncytialization of BeWo cells in response to 100 mM forskolin (as judged by the loss of E-cadherin expression) and migration of JEG-3 cells. By comparison, TPβ activation attenuated proliferation (through increased expression of p27 and p53), syncytialization (maintained E-cadherin levels) and migration of trophoblasts. These effects were mediated through highly specific signalling pathways that were largely due to direct protein-protein interactions of the unique intracellular tail of TPβ. 

Conclusion: These data suggest that the TPα isoform, expressed normally on trophoblasts, enhances the processes required for normal placentation. However, activation of the TPβ isoform produces a cellular phenotype consistent with the abnormal placentation observed in PE and indicates that the pathologic upregulation of TPβ in the placenta may play a role in regulating the onset and severity of PE.