Endocrinology, 2021, Vol. 162, No. 4, 1–14 doi:10.1210/endocr/bqab025 Mini-Review Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 Mini-Review Prostaglandin-Endoperoxide Synthase 2 (PTGS2) in the Oviduct: Roles in Fertilization and Early Embryo Development Prashanth Anamthathmakula and Wipawee Winuthayanon School of Molecular Biosciences, Center for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA ORCiD number: 0000-0002-5196-8471 (W. Winuthayanon). Abbreviations: BOEC, bovine oviductal epithelial cell; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; COX-2, cyclooxygenase 2; cPGES, cytosolic prostaglandin E synthase; CRE, cAMP responsive element; CREB, CRE-binding protein; DP, PGD2 receptor; E, embryonic days; E2, estrogen; EP1-4, PGE2 receptors 1-4; FP, PGF2α receptor; ESR, estrogen receptor; GPR30, G protein-coupled estrogen receptor 30; HPGDS, hematopoietic prostaglandin D synthase; LPGDS, lipocalin type prostaglandin D synthase; mPGES, microsomal prostaglandin E synthase; NF-κB, Nuclear factor kappa B; P4, progesterone; PAF, platelet activating factor; PG, prostaglandin; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGES, prostaglandin E synthase; IP, PGI2 receptor; PGF2α, prostaglandin F2α; PGFS, prostaglandin F synthase; PGI2, prostaglandin I2; PGIS, prostaglandin I synthase; PKA, protein kinase A; PPARδ, peroxisome proliferator-activated receptor delta; PTGS2, prostaglandin-endoperoxide synthase 2; STAT3, signal transducer and activator of transcription 3; TXA2, thromboxane; UTJ, uterotubal junction Received: 13 November 2020; Editorial Decision: 28 January 2021; First Published Online: 4 February 2021; Corrected and Typeset: 23 February 2021. Abstract The mammalian oviduct is a dynamic organ where important events such as final mat- uration of oocytes, transport of gametes, sperm capacitation, fertilization, embryo de- velopment, and transport take place. Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), is the rate-limiting enzyme in the production of prostaglandins (PGs) and plays an essential role during early pregnancy, including ovu- lation, fertilization, implantation, and decidualization. Even though the maternal-embryo communication originates in the oviduct, not many studies have systemically investi- gated PTGS2 signaling during early development. Most of the studies investigating im- plantation and decidualization processes in Ptgs2-/- mice employed embryo transfer into the uterus, thereby bypassing the mammalian oviduct. Consequently, an understanding of the mechanistic action as well as the regulation of PTGS2 and derived PGs in ovi- ductal functions is far from complete. In this review, we aim to focus on the importance of PTGS2 and associated PGs signaling in the oviduct particularly in humans, farm ani- mals, and laboratory rodents to provide a broad perspective to guide further research in this field. Specifically, we review the role of PTGS2-derived PGs in fertilization, embryo development, and transport. We focus on the actions of ovarian steroid hormones on PTGS2 regulation in the oviduct. Understanding of cellular PTGS2 function during early embryo development and transport in the oviduct will be an important step toward a ISSN Online 1945-7170 © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected] https://academic.oup.com/endo 1 2 Endocrinology, 2021, Vol. 162, No. 4 better understanding of reproduction and may have potential implication in the assisted reproductive technology. Key Words: cyclooxygenase, embryo transport, fertilization, oviduct, preimplantation embryo development, prostaglandins Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 The mammalian oviduct (Fallopian tube in humans) is a 2A) (3). In mice, PTGS2 is constitutively expressed in the dynamic organ where important events such as final matur- luminal epithelia and smooth muscle cells of the oviduct ation of oocytes, transport of gametes, sperm capacitation, (Fig. 2B) (4). Expression and localization of PTGS2 in the fertilization, embryo development, and embryo transport mammalian oviduct is summarized and listed in Table 1. take place. Anatomically, the Fallopian tube is made up of A loss of PTGS1 enzyme did not show reproductive de- 5 main regions: fimbria, infundibulum, ampulla, isthmus, fects associated with ovulation, fertilization, implantation, and uterotubal junction (UTJ). The fimbria projecting from and decidualization (5) but delayed parturition resulting in the infundibulum is responsible for the ovum pick-up. The neonatal death in mice (6). In contrast, the roles of PTGS2 ampulla is the site of fertilization. The isthmus functions and PTGS2-derived PGs have been intensely investigated as a sperm reservoir and is the region where early embry- for their biological functions in female reproductive pro- onic development takes place postfertilization. Lastly, the cesses while no discernible male reproductive role has UTJ (also known as the intramural portion) exits into the been noted (7, 8). Therefore, we will focus on the action uterine cavity. There are 4 major cell populations in the ovi- of PTGS2 in the context of reproductive physiology with duct: ciliated epithelial, secretory epithelial, stromal, and emphasis on the oviduct in this review. smooth muscle cells. The ciliated epithelial cells create a unidirectional flow of the tubal fluid. The secretory cells produce oviductal fluid which promotes development and PGs Production in the Oviduct protects embryos while in the oviduct. The muscle contrac- In mammals, the oviduct produces significant amounts of tion increases velocity of fluid flow and plays an essential principal bioactive PGs: PGE2, PGF2α, PGD2, and PGI2 (3, role in the embryo transport. The physiological function 4, 9-11). These PGs act locally in an autocrine and/or para- of stromal cells in the oviduct is currently unclear. Overall, crine manner leading to complex synergistic or antagon- the combined actions of ciliated, secretory, and muscle cells istic actions. The PG production from precursor PGH2 is play a pivotal role in fertilization, contribute to embryo de- mediated by specific terminal PG synthases (Fig. 1) and is velopment, and facilitate embryo transport process prior to relatively tissue-specific. Prostaglandin E synthase (PGES) implantation in the uterus (reviewed in (1)). catalyzes the isomerization of PGH2 to PGE2 and exists as Cyclooxygenase (COX; also known as prostaglandin H microsomal PGES (mPGES-1 and mPGES-2) and cytosolic synthase [PGHS] or prostaglandin-endoperoxide synthase PGES (cPGES). Of the 2 microsomal isoforms, mPGES-1 is [PTGS]) is the rate-limiting enzyme in the biosynthesis of an inducible enzyme and is functionally linked to PTGS2 prostaglandins (PGs) and metabolizes arachidonic acid as it efficiently converts PTGS2-derived PGH2 to PGE2, to the precursor prostaglandin H2 (PGH2). Subsequently, while mPGES-2 is coupled to both PTGS1 and PTGS2. PGH2 undergoes rapid conversion by specific prosta- Lastly, cPGES mediates PGE2 biosynthesis and is function- glandin synthases and isomerases into various other ally linked to PTGS1 activity. PGF2α and PGI2 are generated prostanoids such as prostaglandin E2 (PGE2), PGD2, PGF2α, via prostaglandin F synthase (PGFS) and prostaglandin PGI2, and thromboxane (TXA2) (Fig. 1) (2). COX exists I synthase (PGIS), respectively. The synthesis of PGD2 is as 2 isoforms, COX-1 and COX-2, and encoded by sep- mediated by 2 prostaglandin D synthase (PGDS) isoforms, arate genes, PTGS1 and PTGS2, respectively. In this review, lipocalin type PGDS (LPGDS) and hematopoietic PGDS we will refer to COX-1 and COX-2 using the official no- (HPGDS). Expression and localization of PG synthases in menclatures of PTGS1 and PTGS2, respectively. PTGS1 is the oviduct are summarized in Table 1. largely constitutively expressed whereas PTGS2 is highly In humans, local production of PGE2 has been shown to inducible by cytokines, growth factors, and hormones. In be increased during the luteal phase when compared to the the oviduct, PTGS2 is functionally active and is mainly follicular phase (9). PGF2α was also detected in the ampulla localized to epithelial cells (both ciliated and nonciliated) and isthmus during luteal phase (9). PGI2 (also known as cells in mammalian species. In humans, PTGS2 was also de- prostacyclin) and PGE2 were the major PGs in both tubal tected in longitudinal and circular smooth muscle cells but smooth muscle and luminal epithelia (3). The selective at lesser levels when compared to the epithelial cells (Fig. PTGS2 antagonist NS-398 reduced the production of PGI2 Endocrinology, 2021, Vol. 162, No. 4 3 and PGE2 by approximately 66% in minced Fallopian tis- oviduct at the time of ovulation (10). In cows, PGE2 followed sues (3). These data indicate that PGs produced locally in by PGF2α are the predominant PGs secreted in the oviduct human Fallopian tubes are derived from PTGS2 activity. In during the postovulatory phase (11). These findings suggest mice, PGI2 was the most abundant PG in mouse oviducts that the production of various bioactive PGs in the oviduct Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831