Prostaglandin-Endoperoxide Synthase 2 (PTGS2) in the Oviduct: Roles in Fertilization and Early Embryo Development

Prashanth Anamthathmakula; Wipawee Winuthayanon

doi:10.1210/endocr/bqab025

. 2021 Feb 4;162(4):bqab025. doi: 10.1210/endocr/bqab025

Prostaglandin-Endoperoxide Synthase 2 (PTGS2) in the Oviduct: Roles in Fertilization and Early Embryo Development

Prashanth Anamthathmakula ^1,^✉, Wipawee Winuthayanon ^1,^✉

PMCID: PMC7901659 PMID: 33539521

Abstract

The mammalian oviduct is a dynamic organ where important events such as final maturation of oocytes, transport of gametes, sperm capacitation, fertilization, embryo development, 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 ovulation, fertilization, implantation, and decidualization. Even though the maternal-embryo communication originates in the oviduct, not many studies have systemically investigated PTGS2 signaling during early development. Most of the studies investigating implantation 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 oviductal 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 animals, 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 better understanding of reproduction and may have potential implication in the assisted reproductive technology.

Keywords: cyclooxygenase, embryo transport, fertilization, oviduct, preimplantation embryo development, prostaglandins

The mammalian oviduct (Fallopian tube in humans) is a dynamic organ where important events such as final maturation of oocytes, transport of gametes, sperm capacitation, fertilization, embryo development, and embryo transport take place. Anatomically, the Fallopian tube is made up of 5 main regions: fimbria, infundibulum, ampulla, isthmus, and uterotubal junction (UTJ). The fimbria projecting from the infundibulum is responsible for the ovum pick-up. The ampulla is the site of fertilization. The isthmus functions as a sperm reservoir and is the region where early embryonic development takes place postfertilization. Lastly, the UTJ (also known as the intramural portion) exits into the uterine cavity. There are 4 major cell populations in the oviduct: ciliated epithelial, secretory epithelial, stromal, and 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 protects embryos while in the oviduct. The muscle contraction increases velocity of fluid flow and plays an essential role in the embryo transport. The physiological function of stromal cells in the oviduct is currently unclear. Overall, the combined actions of ciliated, secretory, and muscle cells play a pivotal role in fertilization, contribute to embryo development, and facilitate embryo transport process prior to implantation in the uterus (reviewed in (1)).

Cyclooxygenase (COX; also known as prostaglandin H synthase [PGHS] or prostaglandin-endoperoxide synthase [PTGS]) is the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs) and metabolizes arachidonic acid to the precursor prostaglandin H₂ (PGH₂). Subsequently, PGH₂ undergoes rapid conversion by specific prostaglandin synthases and isomerases into various other prostanoids such as prostaglandin E₂ (PGE₂), PGD₂, PGF_2α, PGI₂, and thromboxane (TXA₂) (Fig. 1) (2). COX exists as 2 isoforms, COX-1 and COX-2, and encoded by separate genes, PTGS1 and PTGS2, respectively. In this review, we will refer to COX-1 and COX-2 using the official nomenclatures of PTGS1 and PTGS2, respectively. PTGS1 is largely constitutively expressed whereas PTGS2 is highly inducible by cytokines, growth factors, and hormones. In the oviduct, PTGS2 is functionally active and is mainly localized to epithelial cells (both ciliated and nonciliated) cells in mammalian species. In humans, PTGS2 was also detected in longitudinal and circular smooth muscle cells but at lesser levels when compared to the epithelial cells (Fig. 2A) (3). In mice, PTGS2 is constitutively expressed in the luminal epithelia and smooth muscle cells of the oviduct (Fig. 2B) (4). Expression and localization of PTGS2 in the mammalian oviduct is summarized and listed in Table 1.

Figure 1. — Pathway synthesis of prostaglandins (PGs), their receptors, and downstream secondary messengers. Phospholipase A2 cleaves fatty acids, releasing arachidonic acid. PTGS1 (COX-1) and PTGS2 (COX-2) then subsequently convert arachidonic acid to PGH₂. Lipocalin type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS) are responsible for conversion of PGH₂ to PGD₂, PGES for PGE₂, PGFS for PGF_2α, PGIS to PGI₂, and TXAS (thromboxane A synthase) to TXA₂. PGD₂, PGE₂, PGF_2α, PGI₂, and TXA₂ exert their biological function through binding to PGD₂ receptor 1 and 2 (DP1 and DP2), PGE₂ receptors (EP1-4), PGF receptor (FP), PGI₂ receptor (IP), and TXA₂ receptor (TR), respectively.

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.

Table 1.

PTGS2 and Other Prostaglandin Synthase Enzymes, Prostanoids (PGs), and Their Receptors: Localization in the Oviduct and Function During Fertilization, Preimplantation Embryonic Development and Embryo Transport: the Effect of Pharmacological and Genetic Manipulations of Enzymes are also Indicated

Enzymes → PGs → Receptors	Species	Localization in the oviduct	Function: fertilization, preimplantation, and embryo development and transport
PTGS2 → PGH ₂	Human	PTGS2: epithelial and smooth muscle cells (3)	• Nonspecific PTGS inhibitors either increase (61), decrease (62), or have no effect (63) on tubal motility
	Mouse	PTGS2: epithelial and smooth muscle cells (4)	• NS-398 inhibited blastocyst development in vitro and implantation (39, 52)
			• Ptgs2^-/- females (C57BL6) are infertile with defective ovulation, fertilization, implantation and decidualization (7, 33, 37)
			• Ptgs2^-/- females (CD1) are subfertile with reduced (>50%) in fertilization rate, 2-cell embryos, implantation, term pregnancy, and litter size (41)
	Rat	PTGS2: epithelial cells (19)	• Not reported
	Hamster	PTGS2: epithelial cells (77)	• Nonspecific PTGS inhibitors (indomethacin) had no effect on embryo transport (64)
			• NS-398 (PTGS2-specific antagonist) inhibited PAF-induced ciliary activity in ciliated cell culture (77)
	Cow	PTGS2: epithelial cells (16)	• Sperm exposure increased PTGS2 expression in BOECs (45)
	Pig	PTGS2: epithelial cells (48)	• Artificial insemination (48) and intrauterine seminal plasma infusion (49) increased PTGS2 expression
mPGES-1 and mPGES-2 → PGE ₂ → EP1-EP4 receptors	Human	PGE₂: epithelium and smooth muscle cells (3)	• Intravenous administration of PGE₂:
		Increased PGE₂ detected in the ampulla and isthmus during the luteal phase of the menstrual cycle (9)	◦ induced relaxation (68)
		EP1-4: serosa, luminal epithelial cells, muscular wall, and vessels (12)	◦ inhibited muscle contractions at low doses, stimulated longitudinal muscle contractions at high doses (69)
			◦ stimulated smooth muscle contraction (12, 26)
			◦ restored muscle contractility inhibited by eicosatetraynoic acid (62)
			• NS-398 decreased PGE₂ production in tissue extracts (3)
	Mouse	PGE₂: abundantly detected (4)	• Ep2^-/- females are subfertile with reduced ovulation, fertilization rate and litter size (15)
		Ep4: epithelial cells (95)
		Ep2: smooth muscle cells (95)
	Rat	Not reported	• PGE₂ caused relaxation of the isthmus and UTJ (70)
	Hamster	Not reported	• PGE₂ stimulated ciliary activity in ciliated cell culture (77)
	Rabbit	PGE₂ increased in the fimbria during ovulation (10)	• PGE₂ stimulated ciliary activity of the epithelium in culture (76)
	Horse	EP2 & EP4: epithelial cells, vascular endothelium, smooth muscle and serosa (96)	• PGE₂ accelerated embryo transport to the uterus (71) • PGE₂ relaxed circular smooth muscle in the isthmus (73)
	Cow	mPGES-1 & mPGES-2: epithelial layer of ampulla (97)	• Sperm binding to epithelial cells increased:
		PGE₂: predominant PG secreted during ovulation (11)	◦ PGES expression in ampulla explants (47)
		EP2 & EP4: infundibulum, ampulla, and isthmus (98)	◦ PGES expression and PGE₂ secretion in BOECs (45)
			• PGE₂ suppressed sperm phagocytosis in BOECs (46)
	Pig	mPGES-1: epithelial and smooth muscle cells of ampulla and isthmus (48)	• Artificial insemination increased mPGES-1 expression, PGE₂ secretion and PGE₂/PGF_2α ratio (48)
			• Intrauterine seminal plasma infusion increased PGE₂/PGF_2α ratio (49)
PGIS → PGI ₂ → IP receptor & PPARδ	Humans	PGIS: epithelial cells (3)	• NS-398 reduced PGI₂ production in tissue extracts (3)
		PGI₂: most abundant PG in epithelial and smooth muscle cells (3)	• PGI₂ induced smooth muscle relaxation (3)
		IP: smooth muscle cells (3)	• PGI₂ inhibited circular and stimulated longitudinal muscle contractions (74)
	Mouse	PGIS: luminal epithelial and smooth muscle cells (4)	• NS-398 reduced PGI₂ production (4)
		PGI₂: most abundant PG detected (4)	• PGI₂ was essential for embryo development, blastocyst hatching and implantation (36, 54)
			• PGIS antagonist inhibited blastocyst development in vitro and this was prevented by addition of a PGI₂ analogue (39)
			• Ip^-/- females had no fertility defect (13)
			• Pparδ^-/- embryos have impaired blastocyst formation, hatching and implantation (54)
	Pig	PGIS: mucosa (ampulla) and muscle cells (ampulla and isthmus) (50)	• Iloprost (PGI₂ analogue) reduced polyspermy during in vitro fertilization (43)
		IP: mucosal and muscular layer (50)	• Iloprost lowered mitochondrial membrane potential, decreased apoptosis, and improved blastocyst development in vitro (43)
			• Artificial insemination increased PGIS expression (isthmus) and IP expression (ampulla) (50)
PGFS → PGF _2α → FP receptor	Human	Increased PGF_2α synthesis detected in the ampulla and isthmus during the luteal phase of the menstrual cycle (9)	• PGF_2α stimulated smooth muscle contraction (12, 26, 75)
		FP: serosal, luminal epithelial cells, muscular wall, and vessels (12)	• PGF_2α restored muscle contractility inhibited by eicosatetraynoic acid (62)
	Mouse	Not reported	• Fp^-/- female mice have complete parturition failure (14)
	Rat	FP: ciliated epithelia of isthmus and distal ampulla (near isthmic-ampullary junction) (99)	• Not reported
	Rabbit	PGF_2α increased in the fimbria during ovulation (10)	• PGF_2α stimulated ciliary activity of the epithelium in culture (76)
	Cow	PGF_2α abundantly secreted during ovulation (11)	• Sperm binding increased PGFS expression and PGF_2α production in BOECs (45)
	Pig	PGFS: epithelial cells (48)	• Artificial insemination in superovulated gilts increased PGFS expression and PGF_2α secretion (48)
LPGDS & HPGDS → PGD ₂ → DP1 & DP2 receptors	Mouse	HPGDS: epithelial cells (22)	• HPGDS acts as an inflammation regulator (22)
		PGD₂: second most abundant PG detected (4)
		Dp1: epithelial cells (22)
		Dp2: stromal cells (22)
	Cow	Not reported	• Oocytes incubated with LPGDS antibody reduced sperm-zona pellucida binding, fertilization, and embryonic development (44)

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Abbreviations: BOEC, bovine oviductal epithelial cell; DP, PGD2 receptor; EP1-4, PGE2 receptors 1-4; FP, PGF2α receptor; HPGDS, hematopoietic prostaglandin D synthase; LPGDS, lipocalin type prostaglandin D synthase; mPGES, microsomal prostaglandin E synthase; PAF, platelet activating factor; PG, prostaglandin; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGFS, prostaglandin F synthase; PGI2, prostaglandin I2; PGIS, prostaglandin I synthase; PPARδ, peroxisome proliferator-activated receptor delta; PTGS2, prostaglandin-endoperoxide synthase 2; UTJ, uterotubal junction.

A loss of PTGS1 enzyme did not show reproductive defects associated with ovulation, fertilization, implantation, and decidualization (5) but delayed parturition resulting in neonatal death in mice (6). In contrast, the roles of PTGS2 and PTGS2-derived PGs have been intensely investigated for their biological functions in female reproductive processes while no discernible male reproductive role has been noted (7, 8). Therefore, we will focus on the action of PTGS2 in the context of reproductive physiology with emphasis on the oviduct in this review.

PGs Production in the Oviduct

In mammals, the oviduct produces significant amounts of principal bioactive PGs: PGE₂, PGF_2α, PGD₂, and PGI₂ (3, 4, 9-11). These PGs act locally in an autocrine and/or paracrine manner leading to complex synergistic or antagonistic actions. The PG production from precursor PGH₂ is mediated by specific terminal PG synthases (Fig. 1) and is relatively tissue-specific. Prostaglandin E synthase (PGES) catalyzes the isomerization of PGH₂ to PGE₂ and exists as microsomal PGES (mPGES-1 and mPGES-2) and cytosolic PGES (cPGES). Of the 2 microsomal isoforms, mPGES-1 is an inducible enzyme and is functionally linked to PTGS2 as it efficiently converts PTGS2-derived PGH₂ to PGE₂, while mPGES-2 is coupled to both PTGS1 and PTGS2. Lastly, cPGES mediates PGE₂ biosynthesis and is functionally linked to PTGS1 activity. PGF_2α and PGI₂ are generated via prostaglandin F synthase (PGFS) and prostaglandin I synthase (PGIS), respectively. The synthesis of PGD₂ is mediated by 2 prostaglandin D synthase (PGDS) isoforms, lipocalin type PGDS (LPGDS) and hematopoietic PGDS (HPGDS). Expression and localization of PG synthases in the oviduct are summarized in Table 1.

In humans, local production of PGE₂ has been shown to be increased during the luteal phase when compared to the follicular phase (9). PGF_2α was also detected in the ampulla and isthmus during luteal phase (9). PGI₂ (also known as prostacyclin) and PGE₂ were the major PGs in both tubal smooth muscle and luminal epithelia (3). The selective PTGS2 antagonist NS-398 reduced the production of PGI₂ and PGE₂ by approximately 66% in minced Fallopian tissues (3). These data indicate that PGs produced locally in human Fallopian tubes are derived from PTGS2 activity. In mice, PGI₂ was the most abundant PG in mouse oviducts followed by PGD₂ and PGE₂ (4). PGI₂ production was also markedly reduced by NS-398 treatment (4). In rabbits, PGE₂ and PGF_2α levels increased significantly in the fimbria of the oviduct at the time of ovulation (10). In cows, PGE₂ followed by PGF_2α are the predominant PGs secreted in the oviduct during the postovulatory phase (11). These findings suggest that the production of various bioactive PGs in the oviduct varies in a species-specific manner.

PG Receptor Expression in the Oviduct

PGs act via binding to various G protein-coupled receptors that are specific for each PG. PGD₂, PGE₂, PGF_2α, 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), respectively (Fig. 1) (3, 12). Localization of each PG receptor in the oviduct in different mammalian species are summarized and listed in Table 1. Unlike in Ptgs2^-/- mice, few fertility defects are observed in mice lacking prostanoid receptors. Ip knockout mice are fertile (13), while Fp-deficient mice showed no abnormality in ovulation, fertilization, or implantation but had complete failure of parturition (14). However, Ep2 knockout females were subfertile with reduced ovulation, fertilization rate, and litter size (15). This suggests that (i) prostanoid receptors may not be critical to ovulation, fertilization, and early stages of embryo development or (ii) cross-activation of PGs (because of their similar structure) other than the cognate receptor may occur leading to similar downstream cascades and could indicate compensating mechanisms of PGs signaling pathway.

Steroid Regulation of PTGS2 Expression in Mammalian Oviducts

The ovarian steroids estrogen (E₂) and progesterone (P₄) are major molecules controlling oviductal functions and have direct and opposing effects on ciliated, secretory, and muscle cell populations of the oviduct (reviewed in (1)). Several studies showed that PTGS2 and the production of PGs in the oviduct are also partially governed by the steroid hormones action.

E₂

Treatment of bovine oviduct smooth muscle tissues with E₂ increased the expression of PTGS2, PGES, PGFS, and prostanoid receptors (EP2, EP4, and FP) and the effect was blocked by the estrogen receptor (ESR) antagonists fulvestrant and tamoxifen (16, 17). In cultured bovine oviduct epithelial cell (BOEC) monolayers, E₂ stimulates PGE₂ and PGF_2α production (18). In day 1 pregnant rats, E₂ increased PTGS2 expression in oviductal epithelial cells compared with controls (Fig. 3A-3D) (19). E₂-induced PTGS2 expression led to increased PGs (PGI₂, PGF_2α, and PGE₂) synthesis. The stimulatory effect of E₂ on PGs synthesis was abolished by selective PTGS2 inhibitors (meloxicam and NS-398) (19). Additionally, treatment of tamoxifen inhibited PTGS2 in the oviduct of E₂-treated rats (Fig. 3) (19). Female mice lacking Esr1 in the oviduct epithelial cells had significantly lower levels of HPGDS, PGD₂, and PGF2_α compared with wild-type oviducts (20). In global Esr1^-/- oviducts, Ptgs2 transcript was increased whereas 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 study using primary rat oviductal epithelial cells showed that E₂ or GPR30 agonist (G-1) increased PTGS2 expression and PGE₂ and PGF_2α release, and the effect was completely suppressed by GPR30 antagonist, G-15 (23). Moreover, E₂-induced PTGS2 and PGs production were abolished by the nuclear factor kappa B (NF-κB) inhibitor quinazoline (23). As PTGS2 promoter contains several NF-κB binding sites (24), this suggests that NF-κB plays a critical role in PTGS2 regulation. Overall, these findings indicate that E₂-induced PTGS2 and PGs production in the oviductal epithelial cells are mediated through the membrane GPR30 and classical ESR1-dependent pathway (Fig. 4).

Figure 3. — Estrogen (E₂) induction of PTGS2 protein expression in rat oviductal epithelial cells. Immunostaining using PTGS2 antibody in day 1 pregnant 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.

Figure 4. — Involvement of estrogen (E₂) and progesterone (P₄) on PTGS2 regulation of muscle and ciliated cell activity in the oviduct. P₄ shows no direct effect on PTGS2 expression in the oviduct. In contrast, E₂ increased PTGS2 and prostanoid receptors in the oviduct and the effect was blocked by estrogen receptor (ESR) antagonists (ie, fulvestrant and tamoxifen) and GPR30 antagonist (G-15). E₂-induced PTGS2 causes an increase in PGs production and this effect is blocked by the treatment of selective PTGS2 inhibitors, such as NS-398 and meloxicam. In muscle cells, PGE₂ induces contraction through EP1/EP3 signaling or relaxation via EP2/EP4. PGF_2α shows a stimulatory effect on contractile activity, while PGI₂ increases the muscle relaxation. E₂-induced PGE₂ and PGF_2α production is inhibited by P₄ treatment. Overall, the disruption of P₄ signaling (either through exogenous P₄, synthetic P₄ analog [levonorgestrel] or P₄ receptor inhibitor [mifepristone]) appears to stimulate the expression of prostanoid receptors in the oviduct. In ciliated epithelial cells, PGE₁, PGE₂, and PGF_2α, stimulate ciliary activity. Platelet activating factor (PAF) also increases ciliary beat frequency and the effect is inhibited by NS-398, indicating that PAF signaling in the oviductal ciliated cells is also mediated by PTGS2 activity. However, it is still unclear how E₂ and P₄ modulate PTGS2 and PGs action in the ciliated epithelial cells of the oviduct. E₂ mediated signaling are indicated in purple and P₄ are in orange. Arrows (→) represent stimulatory effect and blunted-end lines (--|) show inhibitory effect.

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 PGF_2α production was blocked by the coadministration of P₄ (18) (Fig. 4). In cows, PGE₂ and PGF_2α levels were lowest during the luteal phase, at which circulating P₄ is elevated (25). In Fallopian tube explants, EP1, EP2, EP3, and FP levels increased after levonorgestrel treatment (a synthetic P₄ analog used in plan B contraceptive pills) (26). Levonorgestrel and mifepristone (a progesterone receptor antagonist) increased EP1 and EP2 protein expression in lumen, muscle, and vessels, whereas P₄ and mifepristone increased FP in vessel of the Fallopian tube (26). Fallopian tube muscular contractility was decreased after P₄ treatment, whereas increased contractility was observed when PGE₂ and PGF_2α were administered (12). Levonorgestrel and mifepristone inhibited muscular contractions in the Fallopian tube explants (26). Both levonorgestrel and mifepristone decreased ciliary beat frequency in the human Fallopian tube in vitro as well as in the rat and mouse oviduct (27, 28). Overall, stimulation or suppression of P₄ signaling using synthetic P₄ or pharmacological inhibition suppresses the oviductal contraction and decreases ciliary activity (Fig. 4). Nevertheless, the exact signaling pathway of P₄, levonorgestrel, or mifepristone on the oviduct function remains unclear and might involve the action of various PGs and their receptors.

Effects of PTGS2 and PGs on Ovarian Function

PTGS2 plays a crucial role during ovulation. In women, treatment with rofecoxib (another PTGS2-selective inhibitor) caused delayed follicular rupture (29). In nonhuman primates, nonspecific inhibition of PTGSs using indomethacin caused oocyte retention in the ovary (30). In rodents, administration of PTGS2-selective inhibitors such as celecoxib or NS-398 led to approximately 40% to 60% reduction in ovulation (31, 32). In mice, Ptgs2^-/- females are infertile partly due to defective ovulation (7). The ovulatory defect in Ptgs2^-/- mice was attributed to both an abnormal cumulus expansion and stigmata formation (33). Furthermore, exogenous PGE₂ restored ovulation in Ptgs2^-/- mice (33). However, a follow-up study demonstrated that follicular growth, oocyte maturation in vivo/in vitro, and in vitro fertilization of the Ptgs2^-/- oocytes were normal, whereas ovulatory process was impaired in adult (2- to 8-month-old) mice (34). Ovulatory defect in Ptgs2^-/- mice was not evident in 3-week-old immature mice, suggesting that the process of ovulation in adult mice may be more dependent on PGs, becoming compromised with aging upon PTGS2 ablation (34). These findings indicate that PGs produced by PTGS2 are responsible for the ovulatory process.

Effects of PTGS2 and PGs on Uterine Function

In humans, polymorphism of PTGS2, 765G>C (rs20417), was associated with increased risk of recurrent implantation failure in Chilean women who underwent different assisted reproductive procedures (35). In mice, wild-type blastocysts failed to implant in Ptgs2^-/- uteri (36, 37), indicating an essential role of PTGS2 during implantation. Moreover, the decidualization response was severely impaired in Ptgs2^-/- uteri (37). The activity of PTGS1 alone cannot compensate for reproductive failures observed in Ptgs2^-/- mice (37). On the contrary, PTGS2 compensated for the loss of PTGS1 activity in Ptgs1^-/- mice during early pregnancy (38). Similarly, in vitro exposure of blastocysts to inhibitors of PTGS2 or PGIS (an enzyme that converts PGH₂ to PGI₂) showed low implantation rates when transferred into day 4 pseudopregnant uteri (39). The implantation potential was restored when blastocysts were cultured in the presence of PGI₂ analogue (39). Furthermore, intrauterine administration of PGIS inhibitor at embryonic day 4 (E4) resulted in degenerated blastocysts and completely inhibited implantation by E5 (39), indicating that PTGS2-derived PGI₂ plays an important role in implantation.

However, there is some discrepancy to the findings regarding the importance of PTGS2 in the uterine function in mouse models. Cheng and Stewart reported that wild-type blastocysts transferred to the pseudopregnant Ptgs2^-/- uteri implanted and developed successfully to term, suggesting that PTGS2 is not essential for implantation, decidualization, and embryo development throughout the pregnancy (40). However, a 24-hour delay in the initial rate of decidual growth after implantation in Ptgs2^-/- recipients was observed, supporting previous studies that PTGS2 is essential in mediating the initial uterine decidual response (40). Additionally, genetic background could contribute to differences in findings from Ptgs2^-/- mouse models. In contrast to the C57BL/6J/129 Ptgs2^-/- complete pregnancy failure, CD1 Ptgs2^-/- mice were subfertile, with a reduction (>50%) in fertilization rate, 2-cell embryos, implantation, term pregnancy, and litter size (41). The improved fertility in CD1 Ptgs2^-/- mice was attributed to the compensatory upregulation of Ptgs1 which partially rescues female infertility in a genetic background-dependent manner (41). Despite the differences, these findings support the notion that PTGS2 signaling is indispensable for normal reproductive function in vivo.

Effects of PTGS2 and PGs on Oviduct Function: Fertilization

Oocytes

Fertilization process requires both functional oocytes and sperm. Several studies have shown that PTGS2 is essential for fertilization. As for the oocytes, pharmacological inhibition of PTGS2 using celecoxib had a tendency to reduce fertilization rate (~50% although not statistically significant) in mice (31). Ptgs2^-/- mice showed the fertilization failure, likely due to impaired oocyte maturation as mentioned above (37). In mice, the reduced fertilization rate in Ep2^-/- females was proposed to be due to an altered oviductal environment and not conducive to fertilization (42). Exogenous treatment of iloprost (a PGI₂ analogue) in culture media reduced the frequency of polyspermy of in vitro fertilized porcine oocytes (19.9% compared with 35.8% in control) (43). Inhibition of LPGDS by preincubating bovine oocytes with LPGDS antibody led to a reduced sperm binding to zona pellucida, fertilization, and embryonic development (44). These findings suggest that the fertilization defect observed in Ptgs2^-/- mice could be potentially due to a disruption of a microenvironment in the oviduct essential for the fertilization process, in addition to the ovulatory and oocyte maturation defect (33).

Sperm

Sperm migration and/or capacitation appear to be normal in the Ptgs2^-/- reproductive tract, as numerous wild-type sperm were present in Ptgs2^-/- oviducts (37). It is unlikely that the fertilization defect is due to an intrinsic defect from the sperm as Ptgs2^-/- males are fertile (7). On the contrary, the presence of sperm alters PTGS2 signaling in the oviduct, which might contribute to optimal environment for the fertilization process. The exposure of various concentrations of motile sperm increased the expression of PTGS2, PGFS, and PGES in BOECs in a dose- and time-dependent manner (45). Additionally, sperm stimulated PGE₂ and PGF_2α secretion from BOEC monolayers, suggesting that sperm-oviductal interaction elevates PG synthesis and may enhance oviductal contractions to facilitate the sperm migration to the site of fertilization (45). PGE₂ also suppressed sperm phagocytosis by polymorphonuclear neutrophils in cultured BOECs (46). A recent study showed that sperm binding to the epithelium resulted in an upregulation of PGES in bovine oviductal ampulla explants (47). In pigs, increased PTGS2 expression was observed in the isthmus and ampulla upon artificial insemination (48). Accordingly, increased mPGES-1 expression, PGE₂ secretion, and PGE₂/PGF_2α ratio were also observed after insemination in these porcine oviducts (48). Similarly, intrauterine infusion of seminal plasma in the porcine oviduct resulted in increased PTGS2 expression and PGE₂/PGF_2α ratio (49). Artificial insemination increased PGIS expression in the isthmus and IP expression in the ampulla of porcine oviducts (50). Overall, these studies indicate that PG synthesis and receptor expression are insemination dependent. It is likely that the oviduct epithelium provides a PG-rich microenvironment that might act to protect sperm by creating a favorable environment for sperm survival and migration. More studies are needed to address the role of PTGS2 signaling in fertilization in vivo, especially to understand whether PTGS2 ablation in the reproductive tract negatively affects sperm function in the oviduct.

Effects of PTGS2 and PGs on Oviduct Function: Embryo Development

Traditionally, PTGS2 signaling has been implicated in the process of embryogenesis. In human preimplantation embryos, PTGS2 is predominantly expressed at later stages of embryogenesis (8-cell, morula, and blastocyst stages) and is localized to trophectoderm (51). In mice, PTGS2 is detectable in embryos from 2-cell to blastocyst stage (52, 53). These findings indicate that preimplantation embryos express PTGS2 and could subsequently contribute toward local production of the PGs within the oviduct.

In addition to its action at the PGI₂ receptor, PGI₂ also acts as an endogenous ligand for peroxisome proliferator-activated receptor delta (PPARδ) and has been shown to be essential for embryo development, blastocyst hatching, and implantation (36, 54). Pparδ^-/- embryos had impaired blastocyst formation, hatching, and implantation (54). PPARδ is also expressed in preimplantation embryos, where oviduct-derived PGI₂ activates PPARδ, thereby enhancing embryo development and implantation potential (54). In mice, increased PGI₂ production in the oviduct is observed at 2 to 3 days post coitus and coincides with the transformation of 2-cell embryos to morulae stage (4). Iloprost exposure during the second and third day of culture enhanced embryo hatching and implantation (55, 56). Pharmacological inhibition of PTGS2 (NS-398) or PGIS (U51605) in mouse 8-cell-stage embryos significantly reduced the blastocyst development in culture (39, 52). Furthermore, inhibition of PTGS2 or PGIS in culture activated caspase-3, resulting in apoptosis in mouse preimplantation embryos and this was prevented by addition of a PGI₂ analogue (39). Porcine embryos treated with iloprost had improved blastocyst development with increased inner cell mass, trophectoderm and total cells, lower mitochondrial membrane potential, and decreased incidence of apoptosis compared to the untreated group (43). These data indicate that PGI₂ improves the overall preimplantation embryo development and quality (43).

In vitro-matured oocytes retrieved from Ptgs2^-/- and Ep2^-/- mice fertilized and underwent normal preimplantation development in culture, suggesting that neither PTGS2 nor EP2 are essential for preimplantation embryo development in vitro (34). Nevertheless, the notion of persisting suboptimal oviductal environment upon PTGS2 ablation in vivo might prove detrimental to the developing embryo and cannot be dismissed. Several studies have reported that co-culturing embryos (human or mouse) with human oviductal epithelia enhanced embryo development, hatching rate, and implantation potential (57-60), which was attributed to the soluble factors produced by oviducts. Whether these soluble factors include PTGS2-generated PGs or not can only be addressed by future studies aimed at specifically investigating the importance of PTGS2 signaling during the development of early embryos in the oviduct using transgenic animal models.

Effects of PTGS2 and PGs on Oviduct Function: Embryo Transport

The transport of embryos is aided by the contraction and the relaxation of smooth muscles as well as ciliary activity of epithelial cells. No single PG or its receptor has been unequivocally identified as the sole mediator of tubal contractility leading to the possibility that different PGs could be involved at different physiological events. Here we will discuss the role of different PTGS2-derived PGs that are involved in muscle contraction and cilia function of the oviduct.

PTGS, PGs, and Muscle Contraction

Nonspecific inhibition of PTGSs using indomethacin, ketoprofen, or eicosatetraynoic acid either increased (61), decreased (62), or had no effect (63) on tubal motility. In hamsters, indomethacin had no effect on embryo transport (64). Therefore, there is an increased interest to elucidate the role of PTGS2-specific signaling on the smooth muscle contractility and embryo tubal transport. Early studies demonstrated that PGEs relaxed while PGFs stimulated smooth muscle activity of the oviduct in vivo in humans, primates, and rabbits (reviewed by (65)). In general, PGE₂ induced contraction through EP1/EP3 signaling or relaxation of smooth muscle via EP2/EP4 receptors (66, 67). Intravenous PGE₂ administration induced relaxation of the Fallopian tubes while stimulating the uterine contraction as measured by recording devices surgically implanted through catheters (68). PGE₂ also inhibited circular smooth muscle contractions in ex vivo muscle preparations from the isthmus region (69). In the same study, PGE₂ exhibited a biphasic response of inhibiting contractility at low concentrations while stimulating at high concentrations in the longitudinal muscle (69). In rats, PGE₂ relaxed isthmus and the UTJ muscle contraction (70). PGE₂ also hastened the oviductal transport of equine embryos to the uterus (71). The effect of PGE₂ appeared to be through an increased PGE₂-specific binding in equine oviduct (72), which subsequently led to a relaxation of circular smooth muscle in the isthmus (73).

In addition to PGE₂, PGI₂ also acts in a paracrine manner, causing relaxation of smooth muscle, and is suggested to play an important role in the initiation of embryo transit through the isthmus in the Fallopian tubes (3). Moreover, the Fallopian tube has been postulated as the source and the target of PGI₂ (3). PGI₂ also inhibited the spontaneous activity of the circular layer while stimulating the longitudinal muscle layer in the Fallopian tube (74). In contrast to PGE₂ and PGI₂, PGF_2α had a stimulatory effect on contractile activity of both circular and longitudinal smooth muscle (75) and restored the contractility inhibited by the nonspecific PTGS inhibitor, eicosatetraynoic acid (62). However, both PGE₂ and PGF_2α have been shown to increase muscle contraction in Fallopian tube explants (12, 26). These varied effects of PGs on muscle contractility in the Fallopian tube could be partly attributed to the multiplicity in PG receptor subtypes and signaling pathways which could result in opposing actions.

PTGS2, PGE₂, and Ciliary Function

In addition to muscle contractility, ciliary activity is also crucial for the transport of gametes and embryos through the oviduct (reviewed in (1)). In the rabbit oviduct culture, PGE₁, PGE₂, and PGF_2α stimulated ciliary activity of ciliated epithelium (76). In hamsters, oviductal ciliated cell cultures in the presence of platelet activating factor (PAF) increased ciliary beat frequency and this was abolished by NS-398 (77). However, actions of PTGS2 and PGs in ciliated cells from these in vitro studies must be interpreted with caution, as culture models may lack crucial paracrine signals from other cell types within the oviduct that affect embryo transport. An in vivo study in hamsters showed that PAF antagonists (TCV-309 and BN-52021) significantly delayed oviductal embryo transport (64). Moreover, the presence of PAF together with PGE₂ produced a synergistic increase of ciliary beating (77), indicating that PAF and PGE₂ pathways are effectively coupled in regulating ciliary function. PAF stimulated PGE₂ production in the oviductal epithelial cells and this was diminished by WEB-2086 (a PAF-receptor blocker) (77). These findings indicate that PGE₂ production in the oviduct is part of the PAF signaling pathway. Human embryos have been reported to produce PAF in culture (78). In the Fallopian tube, the PAF receptor and PAF acetylhydrolase (an enzyme involved in PAF degradation) were co-localized in the oviductal epithelial and stromal cells (79). Overall, regulation of ciliary activity by PAF during the embryo transport appears to be downstream of PTGS2 and PGE₂ production in mammalian oviducts.

Potential Mechanistic Actions of PTGS2 Signaling in the Oviduct

Most of the studies utilizing Ptgs2^-/- mice investigating implantation and decidualization processes use transferred embryos to the uterus, thereby bypassing the oviduct. Even though the maternal-embryo communication originates in the oviduct where it provides a microenvironment for early embryonic development, not many studies have rigorously pursued PTGS2 signaling in the oviduct. Consequently, an understanding of the role of PTGS2 and derived PGs in oviductal functions is far from complete and clearly more research is needed on this topic. Therefore, we postulated the potential mechanism of action of PTGS2 in the oviduct based on studies in other cell types. Studies in different cell types have demonstrated that PGs could exert regulatory feedback actions on PTGS2 expression. In human vascular smooth muscle cells, iloprost induced PTGS2 expression and subsequent PGI₂ production via an adenylyl cyclase/cyclic adenosine monophosphate (cAMP)-dependent mechanism (80). Accordingly, the PTGS2 promoter contains a cAMP responsive element (CRE), which would explain the transcriptional control of PTGS2 by the cAMP pathway (24). In porcine oocytes, iloprost increased the phosphorylation of extracellular signal regulated kinase (ERK) 1/2, thereby activating the mitogen-activated protein kinase (MAPK) pathway (43). In the same study, iloprost also induced protein kinase A (PKA) activity, cAMP response element-binding protein (CREB), and phosphorylated-CREB activation, ultimately leading to an upregulation of PTGS2 (43).

PGE₂ has been shown to potentiate Ptgs2 expression via an adenylyl cyclase/cAMP/PKA-dependent pathway in macrophages (81), monocytes (82), keratinocytes (83). On the contrary, PTGS2 expression was paradoxically inhibited by PGE₂ in porcine aortic smooth muscle cells and rat uterine stromal cells (84, 85). This differential regulation of PTGS2 by PGE₂ could most probably be due to the multiplicity in EP subtypes coupled with differential tissue expression leading to opposing signaling pathways. In a recent study in human amnion fibroblasts, the feed forward induction of PTGS2 by PGE₂ was mediated via EP2, leading to the cAMP signaling cascade and subsequent phosphorylation of CREB and signal transducer and activator of transcription 3 (STAT3), resulting in increased PTGS2 expression (86). In macrophages, the autocrine/paracrine signaling of secreted PGE₂ also led to canonical NF-κB activation and Ptgs2 induction (87). Overall, these studies point out to PG-mediated regulation of PTGS2 in various cell types. However, whether such an autoregulation of PTGS2 through PG-dependent cAMP signal transduction pathway exists in the oviduct is currently unknown. Nevertheless, an autoregulation of PTGS2 either through (i) cAMP signal transduction pathway involving CREB/STAT3 or (ii) NF-κB activation in the oviduct need to be addressed by future studies.

Conclusion and Future Directions

PTGS2 and associated PGs gain significant attraction as they carry out oviduct-specific functions and are important regulators of several processes such as fertilization, embryo development, and transport. PTGS2 signaling in the oviduct establishes an autocrine or a paracrine communication between the gametes, embryos, and oviductal cells which might lead to successful completion of reproductive events associated with fertilization, embryo transport and acts as an embryotrophic/survival factor. With the advent of transgenic and gene targeting approaches using mouse models, future studies should be directed to improve our understanding of cellular PTGS2 function in the oviduct during early embryo development and transport.

First, to definitively determine whether PTGS2 is required for oviduct function, the transfer of in vivo-derived zygotes from wild-type donors into the oviduct of Ptgs2^-/- oviducts must be performed to determine the preimplantation development and transport rate of the embryos. Indirectly, co-culture of wild-type embryos in the oviductal epithelial cells engineered to lack PTGS2 can also be used. Without one of these studies, there is no concrete evidence that PTGS2 has significant biological role in oviductal function. Subsequently, if PTGS2 was shown to be important for the embryo development and transport in vivo, then the role of PTGS2 in each cell type of the oviduct could be determined. This can be accomplished through the cell-type specific deletion of Ptgs2 using Ptgs2^f/f mice (88) breeding with (i) Wnt7a^Cre (89) or Ltf^i-Cre (90) for all oviductal epithelial cell-specific, (ii) Pax8^Cre (91) or Ovgp1^Cre (92) for secretory epithelial cell-specific, (iii) Foxj1^Cre (93) for ciliated epithelial cell-specific, or (iv) Myh11^Cre (94) for smooth muscle cell-specific. These proposed experiments will provide an important step toward a better understanding of PTGS2 function in the oviduct and may have potential implication in the assisted reproductive technology (eg, enhance in vitro fertilization success and improving embryonic development).

Acknowledgments

This study is supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health award number R01HD097087 to W.W.

Glossary

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: PGF_2α 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 F_2α
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

Additional Information

Disclosures: The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article as no data were generated from the current study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing is not applicable to this article as no data were generated from the current study.

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PERMALINK

Prostaglandin-Endoperoxide Synthase 2 (PTGS2) in the Oviduct: Roles in Fertilization and Early Embryo Development

Prashanth Anamthathmakula

Wipawee Winuthayanon

Abstract

Figure 1.

Figure 2.

Table 1.

PGs Production in the Oviduct

PG Receptor Expression in the Oviduct

Steroid Regulation of PTGS2 Expression in Mammalian Oviducts

E₂

Figure 3.

Figure 4.

P₄

Effects of PTGS2 and PGs on Ovarian Function

Effects of PTGS2 and PGs on Uterine Function

Effects of PTGS2 and PGs on Oviduct Function: Fertilization

Oocytes

Sperm

Effects of PTGS2 and PGs on Oviduct Function: Embryo Development

Effects of PTGS2 and PGs on Oviduct Function: Embryo Transport

PTGS, PGs, and Muscle Contraction

PTGS2, PGE₂, and Ciliary Function

Potential Mechanistic Actions of PTGS2 Signaling in the Oviduct

Conclusion and Future Directions

Acknowledgments

Glossary

Abbreviations

Additional Information

Data Availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Prostaglandin-Endoperoxide Synthase 2 (PTGS2) in the Oviduct: Roles in Fertilization and Early Embryo Development

Prashanth Anamthathmakula

Wipawee Winuthayanon

Abstract

Figure 1.

Figure 2.

Table 1.

PGs Production in the Oviduct

PG Receptor Expression in the Oviduct

Steroid Regulation of PTGS2 Expression in Mammalian Oviducts

E2

Figure 3.

Figure 4.

P4

Effects of PTGS2 and PGs on Ovarian Function

Effects of PTGS2 and PGs on Uterine Function

Effects of PTGS2 and PGs on Oviduct Function: Fertilization

Oocytes

Sperm

Effects of PTGS2 and PGs on Oviduct Function: Embryo Development

Effects of PTGS2 and PGs on Oviduct Function: Embryo Transport

PTGS, PGs, and Muscle Contraction

PTGS2, PGE2, and Ciliary Function

Potential Mechanistic Actions of PTGS2 Signaling in the Oviduct

Conclusion and Future Directions

Acknowledgments

Glossary

Abbreviations

Additional Information

Data Availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

E₂

P₄

PTGS2, PGE₂, and Ciliary Function