Potential Sites of Prostaglandin Actions in the Periimplantation Mouse Uterus: Differential Expression and Regulation of Prostaglandin Receptor Genes1

Abstract

Prostaglandins (PGs), especially PGE2 and PGF2alpha, are considered important for blastocyst spacing, implantation, and decidualization in the rodent uterus. However, information regarding uterine sites of PG actions in these processes is lacking. PGE2 or PGF2alpha interacts with specific G protein-coupled membrane receptors. PGE2 receptors are classified into four subtypes, EP1, EP2, EP3, and EP4. While EP1 is coupled to Ca2+ mobilization, activation of EP2 and EP4 triggers stimulation of adenylyl cyclase. In contrast, activation of EP3 inhibits adenylyl cyclase. PGF2alpha receptor (FP) is coupled to stimulation of phospholipase C-inositol trisphosphate (IP3) pathway and Ca2+ mobilization. This investigation demonstrates that PGE2 and PGF2alpha receptor genes are expressed in a temporal and cell-specific manner in the periimplantation mouse uterus. In the mouse, the attachment reaction occurs in the evening (2200-2300 h) of Day 4 of pregnancy and is preceded by embryo spacing, uterine edema, and luminal closure resulting in an intimate apposition of the blastocyst with the uterine luminal epithelium. Expression of EP3 and FP primarily in the circular muscle of the myometrium on Days 3-5 of pregnancy suggests that the circular muscle, not the longitudinal muscle, is the primary target for PG-mediated uterine contractions required for embryo transport, spacing, and/or accommodation in the uterus. In contrast, expression of EP3 in a subpopulation of cells in the stromal bed at the mesometrial side, and of EP4 in the epithelium and stroma on these days, suggests that PGE2 effects on uterine preparation for implantation (such as epithelial cell differentiation, stromal cell proliferation, uterine edema, luminal closure, and increased localized endometrial vascular permeability at the sites of blastocyst attachment) are mediated by these receptor subtypes. Similar expression patterns of EP3 and EP4 in the Day 4 pseudopregnant mouse uterus or in the ovariectomized uterus under combined treatment with estrogen and progesterone suggest that these genes are regulated by ovarian steroids rather than by the embryo during the preimplantation period (Days 1-4). In contrast, the expression of these genes during the postimplantation period (Days 5-8) is associated with the onset of decidualization.

Expression of prostanoid receptor genes in baboon chorion and decidua during pregnancy and parturition

“…However, species differences between the sheep and baboon have previously been demonstrated for EP 2 receptor-mediated effects on myometrium (Senior et al 1993, Crankshaw & Gaspar 1995, Garcia-Villar et al 1995. A number of studies have postulated a role for prostanoid receptors in the endometrium in association with implantation (Yang et al 1997). An important role for PGs in this context is supported by the failure of implantation and decidualisation in mice which are null mutant for the COX-2 gene (Lim et al 1997), and this may be due to the absence of PGI 2 (Lim et al 1999).…”

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…In female reproductive organs such as the ovary and uterus, hormonal exposure induces expression of the EP subtypes in a cell type-specific manner. EP4 is expressed in the mouse ovary (Segi et al, 2003) and in the human (Milne et al, 2001;Astle et al, 2005), baboon , mouse Yang et al, 1997), rat (Blesson et al, 2012), and guinea pig (Terry et al, 2008) uterus, although Arosh et al (2003Arosh et al ( , 2004 reported that EP4 mRNA was undetectable in the bovine uterus.…”

Two Concepts on the Immunological Aspect of Blastocyst Implantation

“…PGE 2 exerts its effects by binding one of 4 receptors, EP 1 , EP 2 , EP 3 , and EP 4 . During the periimplantation period EP 1 , EP 3 , and EP 4 genes are expressed in the uterus in a spatio-temporal manner, suggesting compartmentalized actions of PGE 2 during this period [56]. EP 2 mRNA is exclusively expressed in the luminal epithelium and appears to be involved in its differentiation for uterine receptivity.…”