Contribution of Prostaglandin Transporter OATP2A1/SLCO2A1 to Placenta-to-Maternal Hormone Signaling and Labor Induction.

Mai Inagaki,Emi Nakashima,Takeo Nakanishi,Shin-Ichi Akanuma,Masanori Tachikawa,Masatoshi Tomi,Hiroaki Shimada,Saki Noguchi,Tomohiro Nishimura,Ikumi Tamai,Ken-Ichi Hosoya

doi:10.1016/j.isci.2020.101098

Abstract

SummaryWe evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition process. At gestational day (GD) 15.5, OATP2A1 is co-localized with 15-hydroxy-PG dehydrogenase in the mouse placental junctional zone and facilitates PG degradation by delivering PGs to the cytoplasm. Slco2a1 (+/−) females mated with Slco2a1 (−/−) males frequently showed elevated circulating progesterone at GD18.5 and delayed parturition. Progesterone receptor inhibition by RU486 treatment at GD18.5 blocked the delay of parturition. In the junctional zone, PGE2 stimulated placental lactogen II (PL-II) production, resulting in higher expression of PL-II in Slco2a1 (−/−) placenta at GD18.5. Indomethacin treatment at GD15.5 suppressed the PL-II overproduction at GD18.5 in Slco2a1 (−/−) embryo-bearing dams, which promoted progesterone withdrawal and corrected the delayed parturition. These results suggest that extracellular PGE2 reduction by OATP2A1 at mid-pregnancy would be associated with progesterone withdrawal by suppressing PL-II production, triggering parturition onset.

Highlights

Pre-term (42 weeks of gestation) deliveries are leading causes of prenatal death and morbidity worldwide (Liu et al, 2015; Saigal and Doyle, 2008; Challis et al, 2000; Minakami and Sato, 1996)
We evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition process
At gestational day (GD) 15.5, OATP2A1 is co-localized with 15-hydroxy-PG dehydrogenase in the mouse placental junctional zone and facilitates PG degradation by delivering PGs to the cytoplasm

Summary

Introduction

Pre-term (42 weeks of gestation) deliveries are leading causes of prenatal death and morbidity worldwide (Liu et al, 2015; Saigal and Doyle, 2008; Challis et al, 2000; Minakami and Sato, 1996). Prostaglandins (PGs), especially PGF2a and PGE2, have a uterotonic action in parturition and have been used clinically for induction of labor (Khan et al, 2008). Uterine PGF2a production is induced via COX-1, and PGF2a circulates to the ovary and binds to PGF2a receptor to initiate corpus luteum regression, i.e., luteolysis (Sugimoto et al, 1997). Since progesterone is mainly produced by the corpus luteum, luteolysis reduces the circulating level of progesterone at late pregnancy (Malassine et al, 2003). Progesterone withdrawal, due to the decline of circulating progesterone levels, triggers COX-2 expression in the uterus, and COX-2-derived PGE2 and PGF2a promote uterine myometrial contraction and cervical ripening (Tsuboi et al, 2003), resulting in induction of labor. Autocrine/paracrine signaling by PGs is an important determinant of the timely onset of labor

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