G-protein coupled receptors expressed in human uterine tissues: Novel targets for labour management

Abstract ID 100351 Poster Board 362 Introduction: Preterm birth is the leading cause of neonatal mortality and morbidity, yet pharmacological options for management of labour do not effectively prevent preterm birth and are associated with adverse side effects. For successful labour, the upper segment of the uterus must contract, and the lower segment must relax to allow passage of the fetus. G-protein coupled receptors (GPCR) are a promising area for target discovery, particularly those that couple via G αq or G αs subunits, which are implicated in smooth muscle contraction or relaxation, respectively. However, GPCR expression in the human uterus is largely unknown. Hypothesis: We hypothesize that the transition from quiescent pregnancy to active, contractile labour is mediated by changes in the expression of pro-quiescent (Gαs) and pro-contractile (Gαq) GPCRs. Aim: To profile GPCR expression in human myometrium (uterine smooth muscle) to identify novel GPCRs within the pregnant human uterus as potential drug targets for the clinical management of labour. Methods: Myometrial (n = 6) tissue biopsied at term Cesarean section was analyzed for the expression of 370 GPCRs using real time reverse transcriptase PCR. Additional myometrium (biopsied from both the upper and lower segments of the uterus) in n = 4-6/group (term not-in-labour TNL, term labour TL, preterm not-in-labour PTNL, and preterm labour PTL) were analyzed via RNA sequencing to determine changes with labour, gestation, and spatial origin. Results: In total, 330 and 307 GPCRs were identified in the upper and lower myometrium, respectively. Of which, 4 and 40 GPCRs, respectively, were significantly differentially expressed with labour (preterm or term). Of interest, purinergic receptor P2Y (P2RY2, Gαq-coupled) expression was 1.9±0.5-log2fold higher with term labour (p-adj = 0.02) and pyramidinergic receptor P2Y, (P2RY6, Gαq-coupled) expression was 3.0±0.7-log2fold higher with preterm labour (p-adj = 0.007) in the lower myometrium. Term labour was also associated with 1.5±0.5-log2fold lower expression of arginine vasopressin receptor 2 (AVPR2, Gαs-coupled) in the lower myometrium (p-adj = 0.04). Spatial differences (upper vs lower) in GPCR expression were observed in term uteri (27 differentially expressed GPCRs), and to a much lesser extent in preterm uteri (4 differentially expressed GPCRs), suggesting that spatial regionalization is characteristic of term uteri, but not preterm. Conclusion: These results suggest that the maintenance of quiescence and onset of labour may be regulated by multiple GPCRs, particularly in the lower segment myometrium. In addition, spatial regionalization of select GPCRs within the pregnant uterus may be utilized to promote contraction and/or quiescence. The potential role of purinergic receptors as ligand-gated ion channels in the human uterus presents a novel direction for insight into the mechanism of labour and uterine contraction. Future work will aim to functionally screen these GPCRs to identify novel targets for treating preterm labour.