Role for the thromboxane A2 receptor β-isoform in the pathogenesis of intrauterine growth restriction.

Katie L Powell,Vitomir Tasevski,Sharon A Mccracken,Jonathan M Morris,Veronica Stevens,Dannielle H Upton,Ann M Simpson,Yan Cheng,Anthony W Ashton

doi:10.1038/srep28811

Abstract

Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications, including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans.

Highlights

Intrauterine growth restriction (IUGR) is defined as failure of the fetus to reach its genetically pre-determined growth potential[1,2]
We propose that dysregulation of thromboxane receptor (TP) isoform expression in the placenta is a significant cause of spontaneous IUGR in human pregnancy, which is amenable to targeted therapy to prevent both the short and long term mortality and morbidity associated with this condition
We assessed TP isoform expression in third trimester placental tissue from “normal” uncomplicated pregnancies and those affected by IUGR (Table 1)

Summary

Introduction

Intrauterine growth restriction (IUGR) is defined as failure of the fetus to reach its genetically pre-determined growth potential[1,2]. Placentae of growth restricted pregnancies are smaller in weight, have reduced number and diameter of villi and a reduction in the number and area of capillaries within the villi indicating impaired vascularisation and branching angiogenesis[10,11,12] They exhibit greater rates of infarction, fetal vessel thrombosis and chronic villitis than the placentae of normal pregnancies[13]. Infusion of TXA2 analogues (such as U46619 and STA2) into rodents produces a IUGR-like syndrome characterised by a 10–15% reduction in pup weight, which persisted until 28 and 77 days post-partum for male and female offspring, respectively[25,26,27] The pups from these pregnancies exhibit a pattern of growth restriction characteristic of asymmetrical IUGR with reduced body/liver weight with sparing of brain changes in weight or energy metabolites[25,28,29]. We propose that dysregulation of TP isoform expression in the placenta is a significant cause of spontaneous IUGR in human pregnancy, which is amenable to targeted therapy to prevent both the short and long term mortality and morbidity associated with this condition

Methods

Results

Conclusion