No abstract

Successful implantation is the result of reciprocal interactions between the implantation-competent blastocyst and receptive uterus. Although various cellular aspects and molecular pathways of this dialogue have been identified, a comprehensive understanding of the implantation process is still missing. The receptive state of the uterus, which lasts for a limited period, is defined as the time when the uterine environment is conducive to blastocyst acceptance and implantation. A better understanding of the molecular signals that regulate uterine receptivity and implantation competency of the blastocyst is of clinical relevance because unraveling the nature of these signals may lead to strategies to correct implantation failure and improve pregnancy rates. Gene expression studies and genetically engineered mouse models have provided valuable clues to the implantation process with respect to specific growth factors, cytokines, lipid mediators, adhesion molecules, and transcription factors. However, a staggering amount of information from microarray experiments is also being generated at a rapid pace. If properly annotated and explored, this information will expand our knowledge regarding yet-to-be-identified unique, complementary, and/or redundant molecular pathways in implantation. It is hoped that the forthcoming information will generate new ideas and concepts for a process that is essential for maintaining procreation and solving major reproductive health issues in women.

The present investigation studied the influ-

We have established a model that shows cooperative interaction among preimplantation embryos and the role of growth factors on their development and growth.Two-cell mouse embryos cultured singly in 25-ed microdrops had inferior development to blastocysts and lower cell numbers per blastocyst compared with those cultured in groups of 5 or 10. The inferior development of singly cultured embryos was markedly improved by addition of epidermal growth factor (EGF) or transforming growth factor a or 31 (TGF-a or TGF-131) to the culture medium. The stage of embryonic development, primarily affected by these treatments, was between eight-cell/morula and blastocyst. Furthermore, bIastocysts developed from eight-cell embryos cultured in groups or singly in the presence ofEGF showed a higher incidence ofzona hatching compared with those cultured singly in the absence of EGF. (P4) and estrogen (E) reverses these defects (1, 2). These observations suggest that although certain factors of embryonic origin participate in an autocrine regulation of embryonic development, the full complement of preimplantation embryo development requires additional paracrine factors that originate from the reproductive tract under the influence of P4 and E. There is no convincing evidence for direct effects of P4 and/or E on preimplantation embryo development. The concept of autocrine regulation of preimplantation embryo development and differentiation is further supported by the fact that preimplantation embryos can develop into blastocysts in vitro in a simple medium (3). However, embryonic growth rate is slower in vitro and there are fewer cells in in vitro-grown blastocysts (4). This suggests that absence of growth factors of reproductive tract origin and/or dilution of these factors released by the embryos in the culture medium are responsible for retarded development of preimplantation embryos in vitro. This contention is further supported by recent reports of synthesis of several growth factors by the preimplantation embryo (5) and the uterus (6-8). Thus growth factors produced by the preimplantation embryo and/or the reproductive tract are available to influence embryonic development and function in an autocrine/paracrine manner. If growth factors produced by the preimplantation embryo act on them, then it can be postulated that preimplantation embryos cultured in a small number in a defined volume of culture medium will show inferior development compared with those cultured as a large group. This could reflect a greater dilution of the growth factors secreted from a small number of cultured embryos into the medium compared with those cocultured in a larger group. This inferior development should then be corrected by addition of growth factors in the culture medium. To test this hypothesis, we have developed a unique model to examine the cooperative interaction among embryos and the role of growth factors and their interactions on preimplantation embryo development in vitro.

We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. However, the candidate PG(s) that participates in these processes and the mechanism of its action remain undefined. Using COX2-deficient mice and multiple approaches, we demonstrate herein that COX2-derived prostacyclin (PGI 2 ) is the primary PG that is essential for implantation and decidualization. Several lines of evidence suggest that the effects of PGI 2 are mediated by its activation of the nuclear hormone receptor PPAR␦, demonstrating the first reported biologic function of this receptor signaling pathway.