sign in sign up
<<
Home , Cyclooxygenase, Prostacyclin, Prostaglandin H2, Prostanoid, PTGS1

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 -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 , Washington State University, Pullman, WA 99164, USA

ORCiD number: 0000-0002-5196-8471 (W. Winuthayanon).

Abbreviations: BOEC, bovine oviductal epithelial ; cAMP, cyclic adenosine monophosphate; COX, ; COX-2, cyclooxygenase 2; cPGES, cytosolic synthase; CRE, cAMP responsive element; CREB, CRE-binding ; DP, PGD2 ; 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 ; NF-κB, Nuclear factor kappa B;

P4, progesterone; PAF, activating factor; PG, prostaglandin; PGD2, ; PGE2, ; PGES, prostaglandin E synthase; IP, PGI2 receptor; PGF2α, prostaglandin F2α; PGFS, prostaglandin F synthase; PGI2, prostaglandin

I2; PGIS, prostaglandin I synthase; PKA, ; PPARδ, peroxisome proliferator-activated receptor delta; PTGS2, prostaglandin-endoperoxide synthase 2; STAT3, signal transducer and activator of 3; TXA2, ; 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 in the production of (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 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 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 as it efficiently converts PTGS2-derived PGH2 to PGE2, to the precursor (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 into various other ally linked to PTGS1 activity. PGF2α and PGI2 are generated 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 , 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 , 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- ) 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 by Washington State University, [email protected] on 23 February 2021 followed by PGD2 and PGE2 (4). PGI2 production was also varies in a species-specific manner. markedly reduced by NS-398 treatment (4). In rabbits, PGE2 and PGF2α levels increased significantly in the fimbria of the PG Receptor Expression in the Oviduct PGs act via binding to various G protein-coupled recep-

tors that are specific for each PG. PGD2, PGE2, PGF2α,

and PGI2 exert their biological function through binding

to PGD2 receptor 1 and 2 (DP1 and DP2), PGE2 receptors

(EP1-4), PGF receptor (FP), and PGI2 receptor (IP), re- spectively (Fig. 1) (3, 12). Localization of each PG receptor in the oviduct in different mammalian species are sum- marized and listed in Table 1. Unlike in Ptgs2-/- mice, few fertility defects are observed in mice lacking receptors. Ip knockout mice are fertile (13), while Fp- deficient mice showed no abnormality in ovulation, fer- tilization, or implantation but had complete failure of parturition (14). However, Ep2 knockout females were Figure 1. Pathway synthesis of prostaglandins (PGs), their receptors, subfertile with reduced ovulation, fertilization rate, and and downstream secondary messengers. A2 cleaves litter size (15). This suggests that (i) prostanoid receptors fatty acids, releasing arachidonic acid. PTGS1 (COX-1) and PTGS2 may not be critical to ovulation, fertilization, and early (COX-2) then subsequently convert arachidonic acid to PGH2. Lipocalin type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS) are respon- stages of embryo development or (ii) cross-activation of sible for conversion of PGH to PGD , PGES for PGE , PGFS for PGF , 2 2 2 2α PGs (because of their similar structure) other than the PGIS to PGI , and TXAS (thromboxane A synthase) to TXA . PGD , PGE , 2 2 2 2 cognate receptor may occur leading to similar down- PGF2α, PGI2, and TXA2 exert their biological function through binding stream cascades and could indicate compensating mech- to PGD2 receptor 1 and 2 (DP1 and DP2), PGE2 receptors (EP1-4), PGF receptor (FP), PGI2 receptor (IP), and TXA2 receptor (TR), respectively. anisms of PGs signaling pathway.

Figure 2. Expression of PTGS2 protein in human and mouse oviducts. (A) In human Fallopian tubes, immunohistochemical analysis showed that PTGS2 is mainly expressed in the nonciliated (open arrow) and ciliated (closed arrow) epithelial cells. Abbreviations: L; longitudinal muscle cells, C; circular muscle cells. Left and middle panels are cross-section from human Fallopian tissues. Reprinted/Reproduced from (3) with permission from Oxford University Press. (B) In mice, PTGS2 protein was detected in luminal epithelial cells (arrow), smooth muscle cells (arrowhead), and vascular endothelial cells (dashed arrow). Right panels are mouse oviductal tissues. Top panel is the tissue incubated with PTGS2 antibody and the bottom is the negative control. Bar ≈ 100 μm. Reprinted/Reproduced from (4) with permission from Oxford University Press. 4 Endocrinology, 2021, Vol. 162, No. 4

2 α /PGF 2 Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 secretion and PGE 2 ratio ( 49 ) 2 α /PGF 2 : 2 secretion in BOECs ( 45 ) 2 production in tissue extracts ( 3 ) 2 females (C57BL6) are infertile with defective ovulation, fertilization, fertilization, females (C57BL6) are infertile with defective ovulation, 2-cell females (CD1) are subfertile with reduced (>50%) in fertilization rate, -/- -/- females are subfertile with reduced ovulation, fertilization rate and litter size ( 15 ) females are subfertile with reduced ovulation, caused relaxation of the isthmus and UTJ ( 70 ) stimulated ciliary activity in ciliated cell culture ( 77 ) stimulated ciliary activity of the epithelium in culture ( 76 ) accelerated embryo transport to the uterus ( 71 ) relaxed circular smooth muscle in the isthmus ( 73 ) suppressed sperm phagocytosis in BOECs ( 46 ) 2 2 2 2 2 2 -/- PGES expression in ampulla explants ( 47 ) PGES expression and PGE induced relaxation ( 68 ) stimulated longitudinal muscle inhibited muscle contractions at low doses, stimulated smooth muscle contraction ( 12 , 26 ) restored muscle contractility inhibited by eicosatetraynoic acid ( 62 ) contractions at high doses ( 69 ) ◦ ◦ ◦ ◦ ◦ ◦ NS-398 decreased PGE Sperm binding to epithelial cells increased: implantation and decidualization ( 7 , 33 37 ) Ptgs2 and litter size ( 41 ) term pregnancy, implantation, embryos, Not reported Nonspecific PTGS inhibitors (indomethacin) had no effect on embryo transport ( 64 ) PAF-induced ciliary activity in ciliated NS-398 (PTGS2-specific antagonist) inhibited cell culture ( 77 ) Sperm exposure increased PTGS2 expression in BOECs ( 45 ) PTGS2 expression Intravenous administration of PGE ratio ( 48 ) Intrauterine seminal plasma infusion increased PGE ), or have no effect ( 63 ) decrease ( 62 ), Nonspecific PTGS inhibitors either increase ( 61 ), on tubal motility NS-398 inhibited blastocyst development in vitro and implantation ( 39 , 52 ) Ptgs2 Ep2 Artificial insemination increased mPGES-1 expression, PGE Artificial insemination increased mPGES-1 expression, Artificial insemination ( 48 ) and intrauterine seminal plasma infusion 49 increased • • PGE • PGE • PGE • PGE • PGE • • • PGE • • • • • • • • • • • • Function: fertilization, preimplantation, and embryo development and transport development and embryo preimplantation, Function: fertilization, ) detected in the ampulla and isthmus 2 : epithelium and smooth muscle cells ( 3 ) : abundantly detected ( 4 ) increased in the fimbria during ovulation ( 10 ) : predominant PG secreted during ovulation ( 11 ) 2 2 2 2 during the luteal phase of menstrual cycle ( 9 wall, and vessels ( 12 ) wall, smooth muscle and serosa ( 96 ) ampulla and isthmus ( 48 ) : infundibulum, ampulla, and isthmus ( 98 ) ampulla, EP2 & EP4 : infundibulum, EP1-4: serosa, luminal epithelial cells, muscular luminal epithelial cells, EP1-4: serosa,

Not reported PGE vascular , EP2 & EP4: epithelial cells, mPGES-1 & mPGES-2: epithelial layer of ampulla ( 97 ) PGE mPGES-1: epithelial and smooth muscle cells of Ep4 : epithelial cells ( 95 ) Ep2: smooth muscle cells ( 95 ) Not reported PGE Increased PGE PTGS2: epithelial cells ( 19 ) PTGS2: epithelial cells ( 77 ) PTGS2: epithelial cells ( 16 ) PTGS2: epithelial cells ( 48 )

PGE PTGS2: epithelial and smooth muscle cells ( 3 ) PTGS2: epithelial and smooth muscle cells ( 4 ) Localization in the oviduct Hamster Rabbit Horse Cow Pig Rat Mouse Rat Hamster Cow Pig Human Human Mouse Species

2 PTGS2 and Other Prostaglandin Synthase , Prostanoids (PGs), and Their Receptors: Localization in the Oviduct and Function During Fertilization, During Fertilization, in the Oviduct and Function Their Receptors: Localization (PGs), and Enzymes, Prostanoids Synthase PTGS2 and Other Prostaglandin → EP1-EP4 receptors

2 PGE Table 1. Table of Pharmacological and Genetic Manipulations Enzymes are also Indicated the Effect Transport: Embryonic Development and Embryo Preimplantation Enzymes → PGs Receptors mPGES-1 and mPGES-2 → PTGS2 → PGH Endocrinology, 2021, Vol. 162, No. 4 5 54 )

2 α Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 production in BOECs ( 45 ) 2 α production in tissue extracts ( 3 ) production ( 4 ) 2 2 analogue ( 39 ) 2 analogue) reduced polyspermy during in vitro fertilization ( 43 ) 2 embryos have impaired blastocyst formation, hatching and implantation ( 54 ) embryos have impaired blastocyst formation, -/- stimulated smooth muscle contraction ( 12 , 26 75 ) restored muscle contractility inhibited by eicosatetraynoic acid ( 62 ) stimulated ciliary activity of the epithelium in culture ( 76 ) induced smooth muscle relaxation ( 3 ) inhibited circular and stimulated longitudinal muscle contractions ( 74 ) was essential for embryo development, blastocyst hatching and implantation ( 36 , was essential for embryo development, 2 α 2 α 2 α female mice have complete parturition failure ( 14 ) 2 2 2 females had no fertility defect ( 13 ) -/- -/- 50 ) Sperm binding increased PGFS expression and PGF secretion ( 48 ) NS-398 reduced PGI Ip lowered mitochondrial membrane potential, decreased apoptosis, and decreased apoptosis, Iloprost lowered mitochondrial membrane potential, improved blastocyst development in vitro ( 43 ) ( Not reported Ppar δ Iloprost (PGI Oocytes incubated with LPGDS antibody reduced sperm-zona pellucida binding, Oocytes incubated with LPGDS antibody reduced sperm-zona pellucida binding, and embryonic development ( 44 ) fertilization, Fp NS-398 reduced PGI HPGDS acts as an regulator ( 22 ) PGIS antagonist inhibited blastocyst development in vitro and this was prevented by addition of a PGI Artificial insemination in superovulated gilts increased PGFS expression and PGF Artificial insemination increased PGIS expression (isthmus) and IP (ampulla) • • • PGI • • • • • • • • PGI • PGI • • PGF • • PGF • • • • PGF Function: fertilization, preimplantation, and embryo development and transport development and embryo preimplantation, Function: fertilization, ) synthesis detected in the ampulla 2 α increased in the fimbria during ovulation abundantly secreted during ovulation ( 11 ) : second most abundant PG detected ( 4 ) 2 : most abundant PG in epithelial and smooth : most abundant PG detected ( 4 ) 2 α 2 α 2 2 (near isthmic-ampullary junction) ( 99 ) and isthmus) ( 50 ) muscle cells ( 3 ) and vessels ( 12 ) ( 10 ) and isthmus during the luteal phase of menstrual cycle ( 9 ) IP: smooth muscle cells ( 3 ) PGIS: luminal epithelial and smooth muscle cells ( 4

IP: mucosal and muscular layer ( 50 ) PGI PGI FP: ciliated epithelia of isthmus and distal ampulla PGF

PGIS: mucosa (ampulla) and muscle cells (ampulla Dp1 : epithelial cells ( 22 ) Dp2 : stromal cells ( 22 ) Not reported Increased PGF Not reported PGF FP: serosal, luminal epithelial cells, muscular wall, muscular wall, luminal epithelial cells, FP: serosal, PGFS: epithelial cells ( 48 ) PGIS: epithelial cells ( 3 ) HPGDS: epithelial cells ( 22 ) PGD

Localization in the oviduct Mouse Rat Rabbit Pig Cow Human Mouse Cow Pig Humans Mouse Species → 2 → FP receptor 2 α → IP receptor & 2 Continued

δ PPAR DP1 & DP2 receptors LPGDS & HPGDS → PGD Table 1. Table Enzymes → PGs Receptors lipocalin type prostaglandin D synthase; hematopoietic prostaglandin D synthase; LPGDS, PGF2 α receptor; HPGDS, PGE2 receptors 1-4; FP, PGD2 receptor; EP1-4, bovine oviductal epithelial cell; DP, Abbreviations: BOEC, prosta - prostaglandin I2; PGIS, prostaglandin F synthase; PGI2, prostaglandin E2; PGFS, prostaglandin D2; PGE2, prostaglandin; PGD2, platelet activating factor; PG, microsomal prostaglandin E synthase; PAF, mPGES, uterotubal junction. prostaglandin-endoperoxide synthase 2; UTJ, receptor delta; PTGS2, peroxisome proliferator-activated δ , glandin I synthase; PPAR PGFS → PGF PGIS → PGI 6 Endocrinology, 2021, Vol. 162, No. 4

Steroid Regulation of PTGS2 Expression in expression led to increased PGs (PGI2, PGF2α, and PGE2)

Mammalian Oviducts synthesis. The stimulatory effect of E2 on PGs synthesis was abolished by selective PTGS2 inhibitors ( The ovarian steroids estrogen (E2) and progesterone (P4)

and NS-398) (19). Additionally, treatment of tamoxifen Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 are major molecules controlling oviductal functions and inhibited PTGS2 in the oviduct of E -treated rats (Fig. 3) have direct and opposing effects on ciliated, secretory, and 2 (19). Female mice lacking Esr1 in the oviduct epithelial muscle cell populations of the oviduct (reviewed in (1)). cells had significantly lower levels of HPGDS, PGD , and Several studies showed that PTGS2 and the production of 2 PGF2 compared with wild-type oviducts (20). In global PGs in the oviduct are also partially governed by the steroid α Esr1-/- oviducts, Ptgs2 transcript was increased whereas hormones action. HPGDS protein was decreased (21, 22). In addition to the

classical genomic pathway, E2 exhibits its activity through G protein-coupled estrogen receptor 30 (GPR30). A recent E2 study using primary rat oviductal epithelial cells showed Treatment of bovine oviduct smooth muscle tissues with that E or GPR30 agonist (G-1) increased PTGS2 expression E increased the expression of PTGS2, PGES, PGFS, and 2 2 and PGE and PGF release, and the effect was completely prostanoid receptors (EP2, EP4, and FP) and the effect 2 2α suppressed by GPR30 antagonist, G-15 (23). Moreover, E - was blocked by the estrogen receptor (ESR) antagonists 2 induced PTGS2 and PGs production were abolished by the fulvestrant and tamoxifen (16, 17). In cultured bovine ovi- nuclear factor kappa B (NF- B) inhibitor quinazoline (23). duct epithelial cell (BOEC) monolayers, E stimulates PGE κ 2 2 As PTGS2 promoter contains several NF- B binding sites and PGF production (18). In day 1 pregnant rats, E in- κ 2α 2 (24), this suggests that NF- B plays a critical role in PTGS2 creased PTGS2 expression in oviductal epithelial cells com- κ regulation. Overall, these findings indicate that 2E -induced pared with controls (Fig. 3A-3D) (19). E2-induced PTGS2

Figure 3. Estrogen (E2) induction of PTGS2 protein expression in rat oviductal epithelial cells. Immunostaining using PTGS2 antibody in day 1 preg- nant rats that were treated with (A-B) vehicle control, (C-D) E2 (1 μg), (E-F) E2 (1 μg) + Tamoxifen (1 mg), and (G-H) Tamoxifen (1 mg) alone. Closed arrows; luminal epithelial cells; open arrow; smooth muscle cells. B, D, F, and H are phase contrast images. Magnification: 40×. (I) Immunoblotting of

PTGS2 (COX-2) and β-ACTIN (loading control) protein expression from rat oviducts that were treated with vehicle (control, C), E2 (1 μg), progesterone

(P4) (4 mg), or E2 (1 μg) +P4 (4 mg). (J) Quantitative analysis of immunoblotting images. *P < 0.05 compared to control. Reprinted/Reproduced from (19) with permission from Elsevier. Endocrinology, 2021, Vol. 162, No. 4 7

PTGS2 and PGs production in the oviductal epithelial cells are mediated through the membrane GPR30 and classical ESR1-dependent pathway (Fig. 4). Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021

P4

In contrast to E2, P4 regulation of PTGS2 signaling in the oviduct is unclear. In rats, P4 had no effect on PTGS2 or

E2-induced PTGS2 expression (Fig. 3I, 3J) (19). Studies in the BOEC culture showed that E2-induced PGE2 and PGF2α production was blocked by the coadministration of P4 (18)

(Fig. 4). In cows, PGE2 and PGF2α levels were lowest during the luteal phase, at which circulating P4 is elevated (25). In Fallopian tube explants, EP1, EP2, EP3, and FP levels in- creased after levonorgestrel treatment (a synthetic P4 analog used in plan B contraceptive pills) (26). Levonorgestrel and Figure 4. Involvement of estrogen (E ) and progesterone (P ) on PTGS2 mifepristone (a progesterone receptor antagonist) increased 2 4 regulation of muscle and ciliated cell activity in the oviduct. P4 shows EP1 and EP2 protein expression in lumen, muscle, and ves- no direct effect on PTGS2 expression in the oviduct. In contrast, E2 in- creased PTGS2 and prostanoid receptors in the oviduct and the effect sels, whereas P4 and mifepristone increased FP in vessel of the Fallopian tube (26). Fallopian tube muscular contract- was blocked by estrogen receptor (ESR) antagonists (ie, fulvestrant and tamoxifen) and GPR30 antagonist (G-15). E -induced PTGS2 causes an ility was decreased after P treatment, whereas increased 2 4 increase in PGs production and this effect is blocked by the treatment of contractility was observed when PGE2 and PGF2α were ad- selective PTGS2 inhibitors, such as NS-398 and meloxicam. In muscle ministered (12). Levonorgestrel and mifepristone inhibited cells, PGE2 induces contraction through EP1/EP3 signaling or relaxation via EP2/EP4. PGF shows a stimulatory effect on contractile activity, muscular contractions in the Fallopian tube explants (26). 2α while PGI increases the muscle relaxation. E -induced PGE and PGF Both levonorgestrel and mifepristone decreased ciliary beat 2 2 2 2α production is inhibited by P4 treatment. Overall, the disruption of P4 frequency in the human Fallopian tube in vitro as well as in signaling (either through exogenous P4, synthetic P4 analog [levonor- gestrel] or P receptor inhibitor [mifepristone]) appears to stimulate the the rat and mouse oviduct (27, 28). Overall, stimulation or 4 expression of prostanoid receptors in the oviduct. In ciliated epithelial suppression of P4 signaling using synthetic P4 or pharmaco- cells, PGE1, PGE2, and PGF2α, stimulate ciliary activity. Platelet activating logical inhibition suppresses the oviductal contraction and factor (PAF) also increases ciliary beat frequency and the effect is in- decreases ciliary activity (Fig. 4). Nevertheless, the exact hibited by NS-398, indicating that PAF signaling in the oviductal cili- ated cells is also mediated by PTGS2 activity. However, it is still unclear signaling pathway of P4, levonorgestrel, or mifepristone on how E and P modulate PTGS2 and PGs action in the ciliated epithelial the oviduct function remains unclear and might involve the 2 4 cells of the oviduct. E2 mediated signaling are indicated in purple and P4 action of various PGs and their receptors. are in orange. Arrows (→) represent stimulatory effect and blunted-end lines (--|) show inhibitory effect.

Effects of PTGS2 and PGs on Ovarian Function whereas ovulatory process was impaired in adult (2- to -/- PTGS2 plays a crucial role during ovulation. In women, 8-month-old) mice (34). Ovulatory defect in Ptgs2 mice treatment with (another PTGS2-selective in- was not evident in 3-week-old immature mice, suggesting hibitor) caused delayed follicular rupture (29). In that the process of ovulation in adult mice may be more de- nonhuman primates, nonspecific inhibition of PTGSs using pendent on PGs, becoming compromised with aging upon indomethacin caused oocyte retention in the ovary (30). In PTGS2 ablation (34). These findings indicate that PGs pro- rodents, administration of PTGS2-selective inhibitors such duced by PTGS2 are responsible for the ovulatory process. as or NS-398 led to approximately 40% to 60% reduction in ovulation (31, 32). In mice, Ptgs2-/- females Effects of PTGS2 and PGs on Uterine Function are infertile partly due to defective ovulation (7). The ovu- latory defect in Ptgs2-/- mice was attributed to both an ab- In humans, polymorphism of PTGS2, 765G>C (rs20417), normal cumulus expansion and stigmata formation (33). was associated with increased risk of recurrent implantation -/- failure in Chilean women who underwent different assisted Furthermore, exogenous PGE2 restored ovulation in Ptgs2 mice (33). However, a follow-up study demonstrated that reproductive procedures (35). In mice, wild-type blasto- -/- follicular growth, oocyte maturation in vivo/in vitro, and cysts failed to implant in Ptgs2 uteri (36, 37), indicating in vitro fertilization of the Ptgs2-/- oocytes were normal, an essential role of PTGS2 during implantation. Moreover, 8 Endocrinology, 2021, Vol. 162, No. 4 the decidualization response was severely impaired in mentioned above (37). In mice, the reduced fertilization rate Ptgs2-/- uteri (37). The activity of PTGS1 alone cannot com- in Ep2-/- females was proposed to be due to an altered ovi- pensate for reproductive failures observed in Ptgs2-/- mice ductal environment and not conducive to fertilization (42).

(37). On the contrary, PTGS2 compensated for the loss of Exogenous treatment of iloprost (a PGI2 analogue) in cul- Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 PTGS1 activity in Ptgs1-/- mice during early pregnancy (38). ture media reduced the frequency of polyspermy of in vitro Similarly, in vitro exposure of blastocysts to inhibitors of fertilized porcine oocytes (19.9% compared with 35.8%

PTGS2 or PGIS (an enzyme that converts PGH2 to PGI2) in control) (43). Inhibition of LPGDS by preincubating bo- showed low implantation rates when transferred into day 4 vine oocytes with LPGDS antibody led to a reduced sperm pseudopregnant uteri (39). The implantation potential was binding to zona pellucida, fertilization, and embryonic de- restored when blastocysts were cultured in the presence of velopment (44). These findings suggest that the fertilization -/- PGI2 analogue (39). Furthermore, intrauterine administra- defect observed in Ptgs2 mice could be potentially due to tion of PGIS inhibitor at embryonic day 4 (E4) resulted in a disruption of a microenvironment in the oviduct essential degenerated blastocysts and completely inhibited implant- for the fertilization process, in addition to the ovulatory ation by E5 (39), indicating that PTGS2-derived PGI2 plays and oocyte maturation defect (33). an important role in implantation. However, there is some discrepancy to the findings re- garding the importance of PTGS2 in the uterine function Sperm in mouse models. Cheng and Stewart reported that wild- Sperm migration and/or capacitation appear to be normal type blastocysts transferred to the pseudopregnant Ptgs2-/- in the Ptgs2-/- reproductive tract, as numerous wild-type uteri implanted and developed successfully to term, sug- sperm were present in Ptgs2-/- oviducts (37). It is unlikely gesting that PTGS2 is not essential for implantation, that the fertilization defect is due to an intrinsic defect decidualization, and embryo development throughout from the sperm as Ptgs2-/- males are fertile (7). On the the pregnancy (40). However, a 24-hour delay in the ini- contrary, the presence of sperm alters PTGS2 signaling in tial rate of decidual growth after implantation in Ptgs2-/- the oviduct, which might contribute to optimal environ- recipients was observed, supporting previous studies that ment for the fertilization process. The exposure of various PTGS2 is essential in mediating the initial uterine de- concentrations of motile sperm increased the expression cidual response (40). Additionally, genetic background of PTGS2, PGFS, and PGES in BOECs in a dose- and could contribute to differences in findings from Ptgs2-/- time-dependent manner (45). Additionally, sperm stimu- -/- mouse models. In contrast to the C57BL/6J/129 Ptgs2 lated PGE2 and PGF2α secretion from BOEC monolayers, complete pregnancy failure, CD1 Ptgs2-/- mice were suggesting that sperm-oviductal interaction elevates PG subfertile, with a reduction (>50%) in fertilization rate, synthesis and may enhance oviductal contractions to fa- 2-cell embryos, implantation, term pregnancy, and litter cilitate the sperm migration to the site of fertilization -/- size (41). The improved fertility in CD1 Ptgs2 mice was (45). PGE2 also suppressed sperm phagocytosis by poly- attributed to the compensatory upregulation of Ptgs1 morphonuclear neutrophils in cultured BOECs (46). A re- which partially rescues female infertility in a genetic cent study showed that sperm binding to the epithelium background-dependent manner (41). Despite the dif- resulted in an upregulation of PGES in bovine oviductal ferences, these findings support the notion that PTGS2 ampulla explants (47). In pigs, increased PTGS2 expres- signaling is indispensable for normal reproductive func- sion was observed in the isthmus and ampulla upon arti- tion in vivo. ficial insemination (48). Accordingly, increased mPGES-1

expression, PGE2 secretion, and PGE2/PGF2α ratio were also observed after insemination in these porcine oviducts Effects of PTGS2 and PGs on Oviduct (48). Similarly, intrauterine infusion of seminal plasma in Function: Fertilization the porcine oviduct resulted in increased PTGS2 expres- sion and PGE2/PGF2α ratio (49). Artificial insemination Oocytes increased PGIS expression in the isthmus and IP expres- Fertilization process requires both functional oocytes and sion in the ampulla of porcine oviducts (50). Overall, these sperm. Several studies have shown that PTGS2 is essen- studies indicate that PG synthesis and receptor expression tial for fertilization. As for the oocytes, pharmacological are insemination dependent. It is likely that the oviduct epi- inhibition of PTGS2 using celecoxib had a tendency to thelium provides a PG-rich microenvironment that might reduce fertilization rate (~50% although not statistically act to protect sperm by creating a favorable environment significant) in mice (31). Ptgs2-/- mice showed the fertiliza- for sperm survival and migration. More studies are needed tion failure, likely due to impaired oocyte maturation as to address the role of PTGS2 signaling in fertilization in Endocrinology, 2021, Vol. 162, No. 4 9 vivo, especially to understand whether PTGS2 ablation in human oviductal epithelia enhanced embryo development, the reproductive tract negatively affects sperm function in hatching rate, and implantation potential (57-60), which the oviduct. was attributed to the soluble factors produced by oviducts.

Whether these soluble factors include PTGS2-generated Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 PGs or not can only be addressed by future studies aimed Effects of PTGS2 and PGs on Oviduct at specifically investigating the importance of PTGS2 Function: Embryo Development signaling during the development of early embryos in the Traditionally, PTGS2 signaling has been implicated in the oviduct using transgenic animal models. process of embryogenesis. In human preimplantation em- bryos, PTGS2 is predominantly expressed at later stages of embryogenesis (8-cell, morula, and blastocyst stages) Effects of PTGS2 and PGs on Oviduct and is localized to trophectoderm (51). In mice, PTGS2 is Function: Embryo Transport detectable in embryos from 2-cell to blastocyst stage (52, The transport of embryos is aided by the contraction and 53). These findings indicate that preimplantation embryos the relaxation of smooth muscles as well as ciliary activity express PTGS2 and could subsequently contribute toward of epithelial cells. No single PG or its receptor has been local production of the PGs within the oviduct. unequivocally identified as the sole mediator of tubal con-

In addition to its action at the PGI2 receptor, PGI2 also tractility leading to the possibility that different PGs could acts as an endogenous for peroxisome proliferator- be involved at different physiological events. Here we will activated receptor delta (PPARδ) and has been shown to be discuss the role of different PTGS2-derived PGs that are essential for embryo development, blastocyst hatching, and involved in muscle contraction and cilia function of the implantation (36, 54). Pparδ-/- embryos had impaired blasto- oviduct. cyst formation, hatching, and implantation (54). PPARδ is also expressed in preimplantation embryos, where oviduct- PTGS, PGs, and Muscle Contraction derived PGI2 activates PPARδ, thereby enhancing embryo development and implantation potential (54). In mice, in- Nonspecific inhibition of PTGSs using indomethacin, creased PGI2 production in the oviduct is observed at 2 to , or eicosatetraynoic acid either increased (61), 3 days post coitus and coincides with the transformation decreased (62), or had no effect (63) on tubal motility. In of 2-cell embryos to morulae stage (4). Iloprost exposure hamsters, indomethacin had no effect on embryo transport during the second and third day of culture enhanced em- (64). Therefore, there is an increased interest to elucidate bryo hatching and implantation (55, 56). Pharmacological the role of PTGS2-specific signaling on the smooth muscle inhibition of PTGS2 (NS-398) or PGIS (U51605) in mouse contractility and embryo tubal transport. Early studies dem- 8-cell-stage embryos significantly reduced the blastocyst onstrated that PGEs relaxed while PGFs stimulated smooth development in culture (39, 52). Furthermore, inhibition muscle activity of the oviduct in vivo in humans, primates, of PTGS2 or PGIS in culture activated caspase-3, resulting and rabbits (reviewed by (65)). In general, PGE2 induced con- in apoptosis in mouse preimplantation embryos and this traction through EP1/EP3 signaling or relaxation of smooth was prevented by addition of a PGI2 analogue (39). Porcine muscle via EP2/EP4 receptors (66, 67). Intravenous PGE2 ad- embryos treated with iloprost had improved blastocyst de- ministration induced relaxation of the Fallopian tubes while velopment with increased inner cell mass, trophectoderm stimulating the uterine contraction as measured by recording and total cells, lower mitochondrial membrane potential, devices surgically implanted through catheters (68). PGE2 and decreased incidence of apoptosis compared to the un- also inhibited circular smooth muscle contractions in ex vivo treated group (43). These data indicate that PGI2 improves muscle preparations from the isthmus region (69). In the the overall preimplantation embryo development and same study, PGE2 exhibited a biphasic response of inhibiting quality (43). contractility at low concentrations while stimulating at high -/- -/- In vitro-matured oocytes retrieved from Ptgs2 and Ep2 concentrations in the longitudinal muscle (69). In rats, PGE2 mice fertilized and underwent normal preimplantation de- relaxed isthmus and the UTJ muscle contraction (70). PGE2 velopment in culture, suggesting that neither PTGS2 nor also hastened the oviductal transport of equine embryos to

EP2 are essential for preimplantation embryo develop- the uterus (71). The effect of PGE2 appeared to be through ment in vitro (34). Nevertheless, the notion of persisting an increased PGE2-specific binding in equine oviduct (72), suboptimal oviductal environment upon PTGS2 ablation which subsequently led to a relaxation of circular smooth in vivo might prove detrimental to the developing em- muscle in the isthmus (73). bryo and cannot be dismissed. Several studies have re- In addition to PGE2, PGI2 also acts in a paracrine manner, ported that co-culturing embryos (human or mouse) with causing relaxation of smooth muscle, and is suggested to 10 Endocrinology, 2021, Vol. 162, No. 4 play an important role in the initiation of embryo transit embryos to the uterus, thereby bypassing the oviduct. through the isthmus in the Fallopian tubes (3). Moreover, Even though the maternal-embryo communication ori- the Fallopian tube has been postulated as the source and the ginates in the oviduct where it provides a microenviron- target of PGI2 (3). PGI2 also inhibited the spontaneous activity ment for early embryonic development, not many studies Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 of the circular layer while stimulating the longitudinal muscle have rigorously pursued PTGS2 signaling in the oviduct. layer in the Fallopian tube (74). In contrast to PGE2 and PGI2, Consequently, an understanding of the role of PTGS2

PGF2α had a stimulatory effect on contractile activity of both and derived PGs in oviductal functions is far from com- circular and longitudinal smooth muscle (75) and restored plete and clearly more research is needed on this topic. the contractility inhibited by the nonspecific PTGS inhibitor, Therefore, we postulated the potential mechanism of eicosatetraynoic acid (62). However, both PGE2 and PGF2α action of PTGS2 in the oviduct based on studies in other have been shown to increase muscle contraction in Fallopian cell types. Studies in different cell types have demon- tube explants (12, 26). These varied effects of PGs on muscle strated that PGs could exert regulatory feedback actions contractility in the Fallopian tube could be partly attributed on PTGS2 expression. In human vascular smooth muscle to the multiplicity in PG receptor subtypes and signaling cells, iloprost induced PTGS2 expression and subsequent pathways which could result in opposing actions. PGI2 production via an adenylyl cyclase/cyclic adenosine monophosphate (cAMP)-dependent mechanism (80). Accordingly, the PTGS2 promoter contains a cAMP re- PTGS2, PGE , and Ciliary Function 2 sponsive element (CRE), which would explain the tran- In addition to muscle contractility, ciliary activity is also scriptional control of PTGS2 by the cAMP pathway (24). crucial for the transport of gametes and embryos through In porcine oocytes, iloprost increased the phosphoryl- the oviduct (reviewed in (1)). In the rabbit oviduct culture, ation of extracellular signal regulated kinase (ERK) 1/2,

PGE1, PGE2, and PGF2α stimulated ciliary activity of ciliated thereby activating the mitogen-activated protein kinase epithelium (76). In hamsters, oviductal ciliated cell cultures (MAPK) pathway (43). In the same study, iloprost also in the presence of platelet activating factor (PAF) increased induced protein kinase A (PKA) activity, cAMP response ciliary beat frequency and this was abolished by NS-398 element-binding protein (CREB), and phosphorylated- (77). However, actions of PTGS2 and PGs in ciliated cells CREB activation, ultimately leading to an upregulation from these in vitro studies must be interpreted with cau- of PTGS2 (43). tion, as culture models may lack crucial paracrine signals PGE2 has been shown to potentiate Ptgs2 expression from other cell types within the oviduct that affect embryo via an adenylyl cyclase/cAMP/PKA-dependent pathway transport. An in vivo study in hamsters showed that PAF in macrophages (81), monocytes (82), keratinocytes (83). antagonists (TCV-309 and BN-52021) significantly delayed On the contrary, PTGS2 expression was paradoxically in- oviductal embryo transport (64). Moreover, the presence hibited by PGE2 in porcine aortic smooth muscle cells and of PAF together with PGE2 produced a synergistic increase rat uterine stromal cells (84, 85). This differential regula- of ciliary beating (77), indicating that PAF and PGE2 path- tion of PTGS2 by PGE2 could most probably be due to the ways are effectively coupled in regulating ciliary function. multiplicity in EP subtypes coupled with differential tissue

PAF stimulated PGE2 production in the oviductal epithelial expression leading to opposing signaling pathways. In a re- cells and this was diminished by WEB-2086 (a PAF-receptor cent study in human amnion fibroblasts, the feed forward blocker) (77). These findings indicate that PGE2 produc- induction of PTGS2 by PGE2 was mediated via EP2, leading tion in the oviduct is part of the PAF signaling pathway. to the cAMP signaling cascade and subsequent phosphor- Human embryos have been reported to produce PAF in cul- ylation of CREB and signal transducer and activator of ture (78). In the Fallopian tube, the PAF receptor and PAF transcription 3 (STAT3), resulting in increased PTGS2 acetylhydrolase (an enzyme involved in PAF degradation) expression (86). In macrophages, the autocrine/paracrine were co-localized in the oviductal epithelial and stromal signaling of secreted PGE2 also led to canonical NF-κB ac- cells (79). Overall, regulation of ciliary activity by PAF tivation and Ptgs2 induction (87). Overall, these studies during the embryo transport appears to be downstream of point out to PG-mediated regulation of PTGS2 in various

PTGS2 and PGE2 production in mammalian oviducts. cell types. However, whether such an autoregulation of PTGS2 through PG-dependent cAMP signal transduc- tion pathway exists in the oviduct is currently unknown. Potential Mechanistic Actions of PTGS2 Nevertheless, an autoregulation of PTGS2 either through Signaling in the Oviduct (i) cAMP signal transduction pathway involving CREB/ Most of the studies utilizing Ptgs2-/- mice investigating im- STAT3 or (ii) NF-κB activation in the oviduct need to be plantation and decidualization processes use transferred addressed by future studies. Endocrinology, 2021, Vol. 162, No. 4 11

Conclusion and Future Directions Data Availability: Data sharing is not applicable to this article as no data were generated from the current study. PTGS2 and associated PGs gain significant attraction as they carry out oviduct-specific functions and are important Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 regulators of several processes such as fertilization, em- References bryo development, and transport. PTGS2 signaling in the 1. Barton BE, Herrera GG, Anamthathmakula P, et al. Roles oviduct establishes an autocrine or a paracrine communi- of steroid hormones in oviductal function. Reproduction. cation between the gametes, embryos, and oviductal cells 2020;159(3):R125-R137. which might lead to successful completion of reproductive 2. Strauss JF, FitzGerald GA. Chapter 4–steroid hormones and other events associated with fertilization, embryo transport and molecules involved in human reproduction. In: Strauss JF, acts as an embryotrophic/survival factor. With the advent Barbieri RL, eds. Yen and Jaffe’s Reproductive Endocrinology of transgenic and targeting approaches using mouse (Eighth Edition). Philadelphia: Elsevier; 2019:75-114.e117. models, future studies should be directed to improve our 3. Huang JC, Arbab F, Tumbusch KJ, Goldsby JS, Matijevic- Aleksic N, Wu KK. Human fallopian tubes express prostacyclin understanding of cellular PTGS2 function in the oviduct (PGI) synthase and and synthesize abundant during early embryo development and transport. PGI. J Clin Endocrinol Metab. 2002;87(9):4361-4368. First, to definitively determine whether PTGS2 is required 4. Huang JC, Goldsby JS, Arbab F, Melhem Z, Aleksic N, for oviduct function, the transfer of in vivo-derived zygotes Wu KK. Oviduct prostacyclin functions as a paracrine factor from wild-type donors into the oviduct of Ptgs2-/- oviducts to augment the development of embryos. Hum Reprod. must be performed to determine the preimplantation de- 2004;19(12):2907-2912. velopment and transport rate of the embryos. Indirectly, 5. Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin co-culture of wild-type embryos in the oviductal epithelial synthase 1 gene disruption in mice reduces arachidonic acid- induced inflammation and indomethacin-induced gastric ulcer- cells engineered to lack PTGS2 can also be used. Without ation. Cell. 1995;83(3):483-492. one of these studies, there is no concrete evidence that 6. Gross GA, Imamura T, Luedke C, et al. Opposing actions of PTGS2 has significant biological role in oviductal function. prostaglandins and oxytocin determine the onset of murine Subsequently, if PTGS2 was shown to be important for the labor. Proc Natl Acad Sci U S A. 1998;95(20):11875-11879. embryo development and transport in vivo, then the role 7. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an of PTGS2 in each cell type of the oviduct could be deter- altered inflammatory response in mice lacking cyclooxygenase mined. This can be accomplished through the cell-type spe- II. Nature. 1995;378(6555):406-409. cific deletion of Ptgs2 using Ptgs2f/f mice (88) breeding with 8. Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the (i) Wnt7aCre (89) or Ltfi-Cre (90) for all oviductal epithelial mouse. Cell. 1995;83(3):473-482. Cre Cre cell-specific, (ii) Pax8 (91) or Ovgp1 (92) for secretory 9. Nieder J, Augustin W. Prostaglandin E and F profiles in human Cre epithelial cell-specific, (iii) Foxj1 (93) for ciliated epithe- fallopian tubes during different phases of the menstrual cycle. Cre lial cell-specific, or (iv) Myh11 (94) for smooth muscle Gynecol Obstet Invest. 1986;21(4):202-207. cell-specific. These proposed experiments will provide an 10. McComb PF, Moon Y. Prostaglandin E and F concentration in important step toward a better understanding of PTGS2 the fimbria of the rabbit fallopian tube increases at the time of function in the oviduct and may have potential implication ovulation. Acta Eur Fertil. 1985;16(6):423-426. 11. Wijayagunawardane MP, Miyamoto A, Cerbito WA, Acosta TJ, in the assisted reproductive technology (eg, enhance in vitro Takagi M, Sato K. Local distributions of oviductal estradiol, fertilization success and improving embryonic development). progesterone, prostaglandins, oxytocin and endothelin-1 in the cyclic cow. Theriogenology. 1998;49(3):607-618. 12. Wånggren K, Lalitkumar PG, Stavreus-Evers A, Ståbi B, Acknowledgments Gemzell-Danielsson K. Prostaglandin E2 and F2alpha receptors This study is supported by the Eunice Kennedy Shriver National in the human Fallopian tube before and after mifepristone treat- Institute of Child Health & Human Development, National Insti- ment. Mol Hum Reprod. 2006;12(9):577-585. tutes of Health award number R01HD097087 to W.W. 13. Murata T, Ushikubi F, Matsuoka T, et al. Altered percep- tion and inflammatory response in mice lacking prostacyclin re- ceptor. Nature. 1997;388(6643):678-682. Additional Information 14. Sugimoto Y, Yamasaki A, Segi E, et al. Failure of partur- Correspondence: Wipawee Winuthayanon, PhD, BSN,Washington ition in mice lacking the . Science. State University, Pullman, WA 99164, USA. E-mail: w.winuthayanon@ 1997;277(5326):681-683. wsu.edu; and Prashanth Anamthathmakula, PhD, Washington State 15. Hizaki H, Segi E, Sugimoto Y, et al. Abortive expansion of University, Pullman, WA 99164, USA. E-mail: p.anamthathmakula@ the cumulus and impaired fertility in mice lacking the prosta- wsu.edu. glandin E receptor subtype EP(2). Proc Natl Acad Sci U S A. Disclosures: The authors have nothing to disclose. 1999;96(18):10501-10506. 12 Endocrinology, 2021, Vol. 162, No. 4

16. Huang N, Wang C, Zhang N, et al. Effect of estrogen on pros- function in female reproduction in mice. Endocrinology. taglandin synthetase in bovine oviduct smooth muscle. Eur J 2001;142(7):3198-3206. Pharmacol. 2018;818:287-293. 32. Mikuni M, Pall M, Peterson CM, et al. The selective prosta- 17. Huang N, Liu B, Dong Z, et al. Prostanoid receptors EP2, EP4, glandin endoperoxide synthase-2 inhibitor, NS-398, reduces and FP are regulated by estradiol in bovine oviductal smooth prostaglandin production and ovulation in vivo and in vitro in Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 muscle. Prostaglandins Other Lipid Mediat. 2015;121(Pt the rat. Biol Reprod. 1998;59(5):1077-1083. B):170-175. 33. Davis BJ, Lennard DE, Lee CA, et al. Anovulation in 18. Wijayagunawardane MP, Choi YH, Miyamoto A, et al. Effect cyclooxygenase-2-deficient mice is restored by prostaglandin E2 of ovarian steroids and oxytocin on the production of prosta- and interleukin-1beta. Endocrinology. 1999;140(6):2685-2695. glandin E2, and endothelin-1 from cow 34. Matsumoto H, Ma W, Smalley W, Trzaskos J, Breyer RM, oviductal epithelial cell monolayers in vitro. Anim Reprod Sci. Dey SK. Diversification of cyclooxygenase-2-derived pros- 1999;56(1):11-17. taglandins in ovulation and implantation. Biol Reprod. 19. Pérez Martínez S, Hermoso M, Farina M, et al. 17-beta- 2001;64(5):1557-1565. Estradiol upregulates COX-2 in the rat oviduct. Prostaglandins 35. Salazar LA, Inostroza M, Jara C, et al. Association of -765G>C Other Lipid Mediat. 2006;80(3-4):155-164. polymorphism of the COX-2 gene with recurrent embryo im- 20. Winuthayanon W, Bernhardt ML, Padilla-Banks E, et al. plantation failure in Southern Chilean women. Clin Chim Acta. Oviductal estrogen receptor α signaling prevents protease- 2010;411(21-22):1822-1824. mediated embryo death. Elife. 2015;4:e10453. 36. Lim H, Gupta RA, Ma WG, et al. Cyclo--2-derived 21. Cerny KL, Ribeiro RA, Jeoung M, Ko C, Bridges PJ. Estrogen prostacyclin mediates embryo implantation in the mouse via Receptor Alpha (ESR1)-dependent regulation of the mouse ovi- PPARdelta. Genes Dev. 1999;13(12):1561-1574. ductal transcriptome. PLoS One. 2016;11(1):e0147685. 37. Lim H, Paria BC, Das SK, et al. Multiple female repro- 22. Bridges PJ, Jeoung M, Shim S, et al. Hematopoetic prosta- ductive failures in cyclooxygenase 2-deficient mice. Cell. glandin D synthase: an ESR1-dependent oviductal epithelial cell 1997;91(2):197-208. synthase. Endocrinology. 2012;153(4):1925-1935. 38. Reese J, Brown N, Paria BC, Morrow J, Dey SK. COX-2 23. Popli P, Sirohi VK, Manohar M, et al. Regulation of compensation in the uterus of COX-1 deficient mice cyclooxygenase-2 expression in rat oviductal epithelial cells: during the pre-implantation period. Mol Cell Endocrinol. Evidence for involvement of GPR30/Src kinase-mediated EGFR 1999;150(1-2):23-31. signaling. J Steroid Biochem Mol Biol. 2015;154:130-141. 39. Pakrasi PL, Jain AK. Cyclooxygenase-2-derived endogenous 24. Kosaka T, Miyata A, Ihara H, et al. Characterization of the prostacyclin reduces apoptosis and enhances embryo via- human gene (PTGS2) encoding prostaglandin-endoperoxide bility in mouse. Prostaglandins Leukot Essent Fatty Acids. synthase 2. Eur J Biochem. 1994;221(3):889-897. 2008;79(1-2):27-33. 25. Wijayagunawardane MP, Miyamoto A, Taquahashi Y, et al. In 40. Cheng JG, Stewart CL. Loss of cyclooxygenase-2 retards de- vitro regulation of local secretion and contraction of the bo- cidual growth but does not inhibit embryo implantation or de- vine oviduct: stimulation by luteinizing , endothelin-1 velopment to term. Biol Reprod. 2003;68(2):401-404. and prostaglandins, and inhibition by oxytocin. J Endocrinol. 41. Wang H, Ma WG, Tejada L, et al. Rescue of female infer- 2001;168(1):117-130. tility from the loss of cyclooxygenase-2 by compensatory 26. Wånggren K, Stavreus-Evers A, Olsson C, Andersson E, up-regulation of cyclooxygenase-1 is a function of genetic Gemzell-Danielsson K. Regulation of muscular contractions makeup. J Biol Chem. 2004;279(11):10649-10658. in the human Fallopian tube through prostaglandins and 42. Tilley SL, Audoly LP, Hicks EH, et al. Reproductive failure and progestagens. Hum Reprod. 2008;23(10):2359-2368. reduced blood pressure in mice lacking the EP2 prostaglandin 27. Zhao W, Zhu Q, Yan M, et al. Levonorgestrel decreases cilia E2 receptor. J Clin Invest. 1999;103(11):1539-1545. beat frequency of human fallopian tubes and rat oviducts 43. Kim JS, Chae JI, Song BS, et al. Iloprost, a prostacyclin ana- without changing morphological structure. Clin Exp Pharmacol logue, stimulates meiotic maturation and early embryonic de- Physiol. 2015;42(2):171-178. velopment in pigs. Reprod Fertil Dev. 2010;22(2):437-447. 28. Bylander A, Lind K, Goksör M, Billig H, Larsson DG. The clas- 44. Gonçalves RF, Staros AL, Killian GJ. Oviductal fluid sical progesterone receptor mediates the rapid reduction of fal- associated with the bovine zona pellucida and the effect on in lopian tube ciliary beat frequency by progesterone. Reprod Biol vitro sperm-egg binding, fertilization and embryo development. Endocrinol. 2013;11:33. Reprod Domest Anim. 2008;43(6):720-729. 29. Pall M, Fridén BE, Brännström M. Induction of delayed fol- 45. Kodithuwakku SP, Miyamoto A, Wijayagunawardane MP. licular rupture in the human by the selective COX-2 inhibitor Spermatozoa stimulate prostaglandin synthesis and se- rofecoxib: a randomized double-blind study. Hum Reprod. cretion in bovine oviductal epithelial cells. Reproduction. 2001;16(7):1323-1328. 2007;133(6):1087-1094. 30. Duffy DM, Stouffer RL. Follicular administration of a 46. Marey MA, Liu J, Kowsar R, et al. Bovine oviduct epithelial cyclooxygenase inhibitor can prevent oocyte release without cells downregulate phagocytosis of sperm by neutrophils: pros- alteration of normal luteal function in rhesus monkeys. Hum taglandin E2 as a major physiological regulator. Reproduction. Reprod. 2002;17(11):2825-2831. 2014;147(2):211-219. 31. Reese J, Zhao X, Ma WG, Brown N, Maziasz TJ, Dey SK. 47. Morillo VA, Akthar I, Fiorenza MF, et al. Toll-like receptor 2 Comparative analysis of pharmacologic and/or gen- mediates the immune response of the bovine oviductal ampulla etic disruption of cyclooxygenase-1 and cyclooxygenase-2 to sperm binding. Mol Reprod Dev. 2020;87(10):1059-1069. Endocrinology, 2021, Vol. 162, No. 4 13

48. Małysz-Cymborska I, Ziecik AJ, Waclawik A, Andronowska A. 66. Senior J, Marshall K, Sangha R, Clayton JK. In vitro character- Effect of hCG and eCG treatments on prostaglandins syn- ization of prostanoid receptors on human myometrium at term thesis in the porcine oviduct. Reprod Domest Anim. pregnancy. Br J Pharmacol. 1993;108(2):501-506. 2013;48(6):1034-1042. 67. Negishi M, Sugimoto Y, Ichikawa A. Molecular mechanisms of 49. Kaczmarek MM, Krawczynski K, Blitek A, Kiewisz J, Schams D, diverse actions of prostanoid receptors. Biochim Biophys Acta. Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 Ziecik AJ. Seminal plasma affects prostaglandin synthesis in the 1995;1259(1):109-119. porcine oviduct. Theriogenology. 2010;74(7):1207-1220. 68. Coutinho EM, Maia HS. The contractile response of the human 50. Małysz-Cymborska I, Andronowska A. Ovarian stimulation uterus, fallopian tubes, and ovary to prostaglandins in vivo. with human chorionic gonadotropin and equine chorionic go- Fertil Steril. 1971;22(9):539-543. nadotropin affects prostacyclin and its receptor expression in 69. Lindblom B, Hamberger L, Wiqvist N. Differentiated con- the porcine oviduct. Domest Anim Endocrinol. 2015;53:17-25. tractile effects of prostaglandins E and F on the isolated circular 51. Wang H, Wen Y, Mooney S, Behr B, Polan ML. Phospholipase A(2) and longitudinal smooth muscle of the human oviduct. Fertil and cyclooxygenase gene expression in human preimplantation Steril. 1978;30(5):553-559. embryos. J Clin Endocrinol Metab. 2002;87(6):2629-2634. 70. Ortega-Moreno J. Influence of prostaglandins E2 and F2 alpha 52. Pakrasi PL, Jain AK. Evaluation of cyclooxygenase 2 derived on passage pressure across the uterotubal junction and isthmus endogenous prostacyclin in mouse preimplantation embryo de- in the rat. Lab Anim. 1995;29(3):327-334. velopment in vitro. Life Sci. 2007;80(16):1503-1507. 71. Weber JA, Freeman DA, Vanderwall DK, Woods GL. 53. Tan HN, Liu Y, Diao HL, Yang ZM. Cyclooxygenases and Prostaglandin E2 hastens oviductal transport of equine em- prostaglandin E synthases in preimplantation mouse embryos. bryos. Biol Reprod. 1991;45(4):544-546. Zygote. 2005;13(2):103-108. 72. Weber JA, Woods GL, Freeman DA, Vanderwall DK. 54. Huang JC, Wun WS, Goldsby JS, Wun IC, Noorhasan D, Wu KK. Prostaglandin E2-specific binding to the equine oviduct. Stimulation of embryo hatching and implantation by prosta- Prostaglandins. 1992;43(1):61-65. cyclin and peroxisome proliferator-activated receptor delta ac- 73. Weber JAW, Woods GL, Lichtenwalner AB. Relaxatory effect of tivation: implication in IVF. Hum Reprod. 2007;22(3):807-814. prostaglandin E2 on circular smooth muscle isolated from the 55. Huang JC, Goldsby JS, Wun WS. Prostacyclin enhances the im- equine oviductal isthmus. Biol Reprod. 1995;52(monograph plantation and live birth potentials of mouse embryos. Hum series 1):125-130. Reprod. 2004;19(8):1856-1860. 74. Lindblom B, Wilhelmsson L, Wiqvist N. The action of prosta- 56. Huang JC, Wun WS, Goldsby JS, Wun IC, Falconi SM, Wu KK. cyclin (PGI2) on the contractility of the isolated circular and lon- Prostacyclin enhances embryo hatching but not sperm motility. gitudinal muscle layers of the human oviduct. Prostaglandins. Hum Reprod. 2003;18(12):2582-2589. 1979;17(1):99-104. 57. Yeung WS, Lau EY, Chan ST, Ho PC. Coculture with hom- 75. Lindblom B, Hamberger L. Cyclic AMP and contractility of the ologous oviductal cells improved the implantation of human human oviduct. Biol Reprod. 1980;22(2):173-178. embryos–a prospective randomized control trial. J Assist 76. Verdugo P, Rumery RE, Tam PY. Hormonal control of ovi- Reprod Genet. 1996;13(10):762-767. ductal ciliary activity: effect of prostaglandins. Fertil Steril. 58. Yeung WS, Ho PC, Lau EY, Chan ST. Improved development of 1980;33(2):193-196. human embryos in vitro by a human oviductal cell co-culture 77. Hermoso M, Barrera N, Morales B, Pérez S, Villalón M. Platelet system. Hum Reprod. 1992;7(8):1144-1149. activating factor increases ciliary activity in the hamster oviduct 59. Xu JS, Cheung TM, Chan ST, Ho PC, Yeung WS. Temporal through epithelial production of prostaglandin E2. Pflugers effect of human oviductal cell and its derived embryotrophic Arch. 2001;442(3):336-345. factors on mouse embryo development. Biol Reprod. 78. O’Neill C, Gidley-Baird AA, Pike IL, Porter RN, Sinosich MJ, 2001;65(5):1481-1488. Saunders DM. Maternal blood platelet physiology and luteal- 60. Xu J, Cheung TM, Chan ST, Ho PC, Yeung WS. Human ovi- phase endocrinology as a means of monitoring pre- and ductal cells reduce the incidence of apoptosis in cocultured postimplantation embryo viability following in vitro fertiliza- mouse embryos. Fertil Steril. 2000;74(6):1215-1219. tion. J in Vitro Fert Embryo Transf. 1985;2(2):87-93. 61. Rustichelli S, Rosa M, Patriarca A, Mariatti M, Crocco R, 79. Velasquez LA, Maisey K, Fernandez R, et al. PAF receptor Grio R. Effects of an antiprostaglandin drug on human fallo- and PAF acetylhydrolase expression in the endosalpinx of the pian tubes in vivo. Clin Exp Obstet Gynecol. 1982;9(1):37-41. human Fallopian tube: possible role of embryo-derived PAF in 62. Lindblom B, Andersson A. Influence of cyclooxygenase inhibi- the control of embryo transport to the uterus. Hum Reprod. tors and arachidonic acid on contractile activity of the human 2001;16(8):1583-1587. Fallopian tube. Biol Reprod. 1985;32(3):475-479. 80. Debey S, Meyer-Kirchrath J, Schrör K. Regulation of 63. Elder MG, Myatt L, Chaudhuri G. The role of prostaglandins cyclooxygenase-2 expression by iloprost in human vascular in the spontaneous motility of the fallopian tube. Fertil Steril. smooth muscle cells. Role of transcription factors CREB and 1977;28(1):86-90. ICER. Biochem Pharmacol. 2003;65(6):979-988. 64. Velasquez LA, Aguilera JG, Croxatto HB. Possible role of 81. Hinz B, Brune K, Pahl A. Prostaglandin E(2) upregulates platelet-activating factor in embryonic signaling during oviductal cyclooxygenase-2 expression in lipopolysaccharide-stimulated transport in the hamster. Biol Reprod. 1995;52(6):1302-1306. RAW 264.7 macrophages. Biochem Biophys Res Commun. 65. Spilman CH, Harper MJ. Effects of prostaglandins on 2000;272(3):744-748. oviductal motility and egg transport. Gynecol Invest. 82. Hinz B, Brune K, Pahl A. Cyclooxygenase-2 expression in 1975;6(3-4):186-205. lipopolysaccharide-stimulated human monocytes is modulated by 14 Endocrinology, 2021, Vol. 162, No. 4

cyclic AMP, prostaglandin E(2), and nonsteroidal anti-inflamma- uterine epithelial gene function. Endocrinology. tory drugs. Biochem Biophys Res Commun. 2000;278(3):790-796. 2014;155(7):2718-2724. 83. Maldve RE, Kim Y, Muga SJ, Fischer SM. Prostaglandin E(2) 91. Bouchard M, Souabni A, Busslinger M. Tissue-specific ex- regulation of cyclooxygenase expression in keratinocytes is me- pression of cre recombinase from the Pax8 locus. Genesis. diated via cyclic -linked prostaglandin receptors. J 2004;38(3):105-109. Downloaded from https://academic.oup.com/endo/article/162/4/bqab025/6128831 by Washington State University, [email protected] on 23 February 2021 Lipid Res. 2000;41(6):873-881. 92. Wu R, Zhai Y, Kuick R, et al. Impact of oviductal versus 84. Karim S, Berrou E, Lévy-Toledano S, Bryckaert M, MacLouf J. ovarian epithelial cell of origin on ovarian endometrioid car- Regulatory role of prostaglandin E2 in induction of cyclo- cinoma phenotype in the mouse. J Pathol. 2016;240(3): oxygenase-2 by a analogue () and 341-351. basic fibroblast in porcine aortic smooth-muscle 93. Zhang Y, Huang G, Shornick LP, et al. A transgenic FOXJ1- cells. Biochem J. 1997;326(Pt 2):593-599. Cre system for gene inactivation in ciliated epithelial cells. Am J 85. Prigent-Tessier A, Pageaux JF, Fayard JM, Lagarde M, Respir Cell Mol Biol. 2007;36(5):515-519. Laugier C, Cohen H. Arachidonic acid up-regulates and pros- 94. Xin HB, Deng KY, Rishniw M, Ji G, Kotlikoff MI. Smooth taglandin E2 down-regulates the expression of pancreatic-type muscle expression of Cre recombinase and eGFP in transgenic and prostaglandin-endoperoxide synthase 2 mice. Physiol Genomics. 2002;10(3):211-215. in uterine stromal cells. Eur J Biochem. 1996;241(3):872-878. 95. Segi E, Haraguchi K, Sugimoto Y, et al. Expression of mes- 86. Lu JW, Wang WS, Zhou Q, Gan XW, Myatt L, Sun K. Activation senger RNA for prostaglandin E receptor subtypes EP4/ of prostaglandin EP4 receptor attenuates the induction of EP2 and cyclooxygenase in mouse periovulatory cyclooxygenase-2 expression by EP2 receptor activation in follicles and oviducts during superovulation. Biol Reprod. human amnion fibroblasts: implications for parturition. Faseb 2003;68(3):804-811. J. 2019;33(7):8148-8160. 96. Ball BA, Scoggin KE, Troedsson MH, Squires EL. 87. Aoki T, Frosen J, Fukuda M, et al. Prostaglandin E2-EP2-NF- Characterization of prostaglandin E2 receptors (EP2, EP4) in kappaB signaling in macrophages as a potential therapeutic target the horse oviduct. Anim Reprod Sci. 2013;142(1-2):35-41. for intracranial aneurysms. Sci Signal. 2017;10(465)eaah6037. 97. Gauvreau D, Moisan V, Roy M, Fortier MA, Bilodeau JF. 88. Ishikawa TO, Herschman HR. Conditional knockout mouse for Expression of prostaglandin E synthases in the bovine oviduct. tissue-specific disruption of the cyclooxygenase-2 (Cox-2) gene. Theriogenology. 2010;73(1):103-111. Genesis. 2006;44(3):143-149. 98. Fontes PK, Castilho AC, Razza EM, Ereno RL, Satrapa RA, 89. Winuthayanon W, Hewitt SC, Orvis GD, Behringer RR, Barros CM. Prostaglandin receptors (EP2 and EP4) and angio- Korach KS. Uterine epithelial estrogen receptor α is dis- tensin receptor (AGTR2) mRNA expression increases in the pensable for proliferation but essential for complete bio- oviducts of Nelore cows submitted to ovarian superstimulation. logical and biochemical responses. Proc Natl Acad Sci U S A. Anim Reprod Sci. 2014;151(3-4):112-118. 2010;107(45):19272-19277. 99. Orlicky DJ, Williams-Skipp C. Immunohistochemical localiza- 90. Daikoku T, Ogawa Y, Terakawa J, Ogawa A, DeFalco T, tion of PGF2 alpha receptor in the rat oviduct. Prostaglandins Dey SK. Lactoferrin-iCre: a new mouse line to study Leukot Essent Fatty Acids. 1993;48(2):185-192.