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Prostaglandins and the Initiation of Blastocyst Implantation and Decidualization

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Prostaglandins and the Initiation of Blastocyst Implantation and Decidualization REPRODUCTIONREVIEW Prostaglandins and the initiation of blastocyst implantation and decidualization Thomas G Kennedy1,2, Carolina Gillio-Meina1 and Sen Han Phang1 Departments of 1Physiology and Pharmacology and 2Obstetrics and Gynaecology, The University of Western Ontario, London, Ontario, N6A 5C1 Canada Correspondence should be addressed to T G Kennedy; Email: [email protected] Abstract The process of blastocyst implantation in mammals is remarkably variable, especially in the extent of trophoblast invasion of the endometrium. In most species studied, the earliest macroscopically identifiable sign of blastocyst implantation is an increase in endometrial vascular permeability in areas adjacent to the blastocysts. This is followed in species with invasive implantation by decidualization, again localized to areas adjacent to the blastocysts. In some species, the application of a stimulus to the endometrium can result in increased endometrial vascular permeability and decidualization. Based initially on studies utilizing inhibitors of prostaglandin (PG) synthesis and more recently on studies using the techniques of transgenics, considerable evidence has accumulated indicating that PGs have an important role in the early events of implantation and artificially induced decidualization. However, which PGs are involved remains controversial. There may be differences between species, and different PGs may be involved at different times. Reproduction (2007) 134 635–643 Introduction trophoblast invasion of the endometrium. In some species there is little or no invasion of trophoblast cells While many different molecules have been implicated in into the endometrium, whereas in others the invasion is the signaling that occurs between the embryo and the extensive (Psychoyos 1973). In those species with no or endometrium at the initiation of implantation, this limited invasion, the endometrium undergoes little review will concentrate on the role of prostaglandins (PGs). More is known about the role of PGs in change in response to implantation. By contrast, in implantation in rodents than in other species, and those species with extensive invasion, the endometrium consequently this is the focus. In addition, the involve- undergoes substantial morphological and functional ment of PGs in artificially induced decidualization is changes referred to as the decidual transformation of reviewed because this reaction has been widely and the endometrium. In most species, this transformation profitably used as a model of implantation. primarily involves the endometrial stroma and is localized to implantation sites. The fibroblastic stromal cells proliferate and differentiate into decidual cells, Initiation of implantation and decidualization which ultimately form the maternal component of the placenta. Implantation of the embryo involves a complex series of In all species investigated – with the exception of sequential interactions between the embryo and the humans – there is an increase in the endometrial uterus, beginning with attachment of the blastocyst to the luminal epithelium of the endometrium and ending with vascular permeability localized to areas adjacent to the blastocysts (Psychoyos 1973). In mice and rats, this the formation of the definitive placenta (see Fig. 1 for the w timing of events in the rat). Embryo–endometrial occurs 4–8 h after the initial blastocyst attachment, is interactions can only be initiated when the embryo and the first macroscopically identifiable event in implan- the endometrium have reached a precise stage of tation, and is commonly taken as defining the beginning maturity; the embryo must be at the blastocyst stage, of implantation. The increase in endometrial vascular and hormone-dependent changes leading to the permeability is thought to be an essential prerequisite for development of a ‘receptive’ endometrium must have decidualization. The localized nature of the endometrial occurred (Psychoyos 1973). vascular permeability response and subsequent decid- The process of blastocyst implantation in mammals is ualization suggests that they occur in response to remarkably variable, especially in the extent of interactions between the embryo and the endometrium. q 2007 Society for Reproduction and Fertility DOI: 10.1530/REP-07-0328 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/24/2021 08:45:00PM via free access 636 T G Kennedy and others Figure 1 Timing of events occurring early in pregnancy in the rat. For mice, uterine closure and the increased endometrial vascular permeability occur w18 h earlier. Signaling between the embryo and the endometrium phenomenon of uterine ‘closure’ which results from the removal of fluid from the uterine lumen in the peri- What is the nature of the signals interchanged between implantation period, thereby bringing the embryo into the embryo and the endometrium? Many different close contact with the luminal epithelium (Martin et al. molecules have been implicated (for reviews, see Paria 1970, Hedlund et al.1972, Ljungkvist 1972). The et al. 2002, Dey et al. 2004). However, it is possible that intimate contact between trophoblastic and epithelial the primary signal given by the blastocyst may be cells that results may be sufficient to signal the presence physical rather than chemical in nature. The fact that a of the blastocyst. Finn & Porter (1975) have summarized variety of non-specific stimuli applied to the endome- the evidence against the initial signal being physical, but trium of rodents and some other species at an did not take into account the possibility that the appropriate time will increase endometrial vascular blastocyst may have an active role in physically permeability and result in decidualization suggests that perturbing the luminal epithelium. When cultured the endometrium is able to produce many, if not all, of in vitro, rat and mouse blastocysts undergo repetitive the signaling molecules involved. In addition, in the contractions and dilations (Cole 1967, Bitton-Casimiri human a conceptus does not have to be present to et al. 1970, Hurst & MacFarlane 1981). If these initiate decidualization; it begins ‘spontaneously’ in the contractions and dilations also occur in vivo, they will late luteal phase of the menstrual cycle with the presumably amplify the physical signal resulting from the differentiation of ‘predecidual cells’ (Kennedy 2003). close contact between the blastocyst and the luminal An exposure of the endometrium to progesterone epithelium. beyond the normal nonpregnant luteal phase results If the initial signal is physical in nature, it will then in a decidual transformation of the endometrium. be necessary for the luminal epithelial cells to convey Presumably because a signal from the embryo is not the signal to the endometrial stroma since it is the required for the initiation of decidualization, the stroma that is vascularized and undergoes deciduali- transformation in the human uterus is generalized rather zation. This would require the conversion of the than localized to the site of implantation. physical signal to a chemical signal by the epithelial Ultrastructural studies of the early stages of implan- cells. In vivo, the luminal epithelium has an essential tation have demonstrated physical interactions between role in decidualization as indicated by the work of trophoblastic cells of the blastocyst and endometrial Ferrando & Nalbandov (1968) and Lejeune et al. luminal epithelial cells. The endometrial vascular (1981), which demonstrated that if the luminal permeability response is preceded by interdigitation of epithelium is destroyed or removed, decidualization microvilli on trophoblastic and epithelial cells, followed cannot be obtained in response to stimuli that would by broad areas of apposition of cell membranes otherwise be deciduogenic. These observations are (Parkening 1976, Enders & Schlafke 1979, Segalen & consistent with the concept that the luminal epi- Chambon 1983). These interactions between the blas- thelium responds to natural and artificial deciduo- tocyst and the endometrium are facilitated by the genic stimuli with the production of compounds Reproduction (2007) 134 635–643 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/24/2021 08:45:00PM via free access Prostaglandins and implantation/decidualization 637 which then result in decidualization. Whether an In addition, the concentrations of PGs are elevated in increase in endometrial vascular permeability can be the areas of increased endometrial vascular permeability obtained in the absence of the luminal epithelium is associated with the initiation of implantation not known. (Kennedy 1977, Evans & Kennedy 1978, Kennedy & Zamecnik 1978, Sharma 1979, Lim et al. 1999, Wang et al. 2004b) and exogenous PGs can reverse, at least PG synthesis and action partially, the effects of indomethacin on implantation (Oettel et al. 1979, Holmes & Gordashko 1980, Garg & PGs are widely produced in mammalian cells from free Chaudhury 1983). arachidonic acid (reviewed by Simmons et al. 2004). In species in which the application of a deciduogenic Arachidonic acid is present mainly in membrane stimulus to the sensitized uterus induces decidualiza- phospholipids and is released from these by the action tion, the extent of the decidual response and the increase of phospholipases, principally phospholipase A2. in endometrial vascular permeability which precedes it Arachidonic acid can be converted
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