Expression and Function of Prostaglandin E2 Receptors in Human Myometrium

Preterm labour occurs in approximately 10 % of pregnancies and shows no signs of abating. Prostaglandin E2 (PGE2) synthesis plays a regulatory role in a number of important processes that are necessary for successful labour. One role for PGE2 is the activation of contractility in the muscle that contracts during labour, the myometrium. The myometrium is theorised to separate into two functional compartments during pregnancy and parturition. During parturition, the fundal region contracts downwards, whilst the lower segment relaxes. PGE2 binds to four G-protein coupled receptors, termed E-series (EP1-4), which modulate a dynamic range of responses due to differential binding of G proteins. The accepted theory for the function of EP receptors in the myometrium, at the time of labour, is that EP1 and EP3 are procontractile receptors whilst EP2 and EP4 receptors are anti-contractile. This thesis studied the compartmental expression of the EP receptors and the signalling pathways they couple to in the pregnant myometrium. EP receptor mRNA and protein do not alter in expression between sample groups, before or after the onset of labour. Further experiments identified EP2 receptors to activate both pro- and anti-labour responses (expression of COX-2 and inhibition of myometrial contractility), interestingly by two distinct G protein signalling pathways, questioning its role as an anti-labour receptor. A novel EP4 receptor agonist also activated cell signalling pathways not previously associated with this receptor. An EP3, but not an EP1, antagonist inhibited spontaneous and PGE2 induced contractility, despite the activation of similar signalling pathways. Overall, this study indicates that the action of an individual EP receptor is more diverse than anticipated, indicating that the myometrium is a complex, dynamic system enabling efficient reprogramming of responsiveness during pregnancy and labour

Expression and function of prostaglandin E2 receptors in human myometrium

Preterm labour occurs in approximately 10 % of pregnancies and shows no signs of abating. Prostaglandin E2 (PGE2) synthesis plays a regulatory role in a number of important processes that are necessary for successful labour. One role for PGE2 is the activation of contractility in the muscle that contracts during labour, the myometrium. The myometrium is theorised to separate into two functional compartments during pregnancy and parturition. During parturition, the fundal region contracts downwards, whilst the lower segment relaxes. PGE2 binds to four G-protein coupled receptors, termed E-series (EP1-4), which modulate a dynamic range of responses due to differential binding of G proteins. The accepted theory for the function of EP receptors in the myometrium, at the time of labour, is that EP1 and EP3 are procontractile receptors whilst EP2 and EP4 receptors are anti-contractile. This thesis studied the compartmental expression of the EP receptors and the signalling pathways they couple to in the pregnant myometrium. EP receptor mRNA and protein do not alter in expression between sample groups, before or after the onset of labour. Further experiments identified EP2 receptors to activate both pro- and anti-labour responses (expression of COX-2 and inhibition of myometrial contractility), interestingly by two distinct G protein signalling pathways, questioning its role as an anti-labour receptor. A novel EP4 receptor agonist also activated cell signalling pathways not previously associated with this receptor. An EP3, but not an EP1, antagonist inhibited spontaneous and PGE2 induced contractility, despite the activation of similar signalling pathways. Overall, this study indicates that the action of an individual EP receptor is more diverse than anticipated, indicating that the myometrium is a complex, dynamic system enabling efficient reprogramming of responsiveness during pregnancy and labour.EThOS - Electronic Theses Online ServiceGBUnited Kingdo