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I Chakraborty, S K Das, J Wang, and S K Dey


Cyclo-oxygenase (COX) is a rate-limiting enzyme that converts arachidonic acid to prostaglandins (PGs) and exists in two isoforms, COX-1 and COX-2. In the rodent, increased uterine vascular permeability at sites of blastocyst apposition is one of the earliest prerequisite events in the implantation process. This event is preceded by generalized uterine edema and luminal closure, and coincides with the initial attachment reaction between the trophectoderm and luminal epithelium. Vasoactive PGs are implicated in these processes. Here we demonstrate that COX genes are differentially regulated in the peri-implantation mouse uterus. During the preimplantation period (days 1–4), the COX-1 gene was expressed in the uterine epithelium mainly on day 4 until the initiation of attachment reaction in the evening after which the expression was downregulated. This COX-1 expression coincides with the generalized uterine edema required for luminal closure. In contrast, the COX-2 gene was expressed in the luminal epithelium and subepithelial stromal cells at the anti-mesometrial pole exclusively surrounding the blastocyst at the time of attachment reaction on day 4 and persisted through the morning of day 5. This uterine gene was not expressed at the sites of blastocyst apposition during progesterone (P4) treated delayed implantation, but was readily induced in the uterus surrounding the activated blastocysts after termination of the delay by estradiol-17β (E2). The results suggest that PG synthesis catalyzed by COX-2 is important for localized increased uterine vascular permeability and attachment reaction. The COX-1 gene that was downregulated from the time of attachment reaction on day 4 was again expressed in the mesometrial and anti-mesometrial secondary decidual beds on days 7 and 8. These results suggest that PGs generated by COX-1 are involved in decidualization and/or continued localized endometrial vascular permeability observed during this period. In contrast, the COX-2 gene, expressed at the anti-mesometrial pole on days 4 and 5, switched its expression to the mesometrial pole from day 6 onward. These results suggest that PGs produced at this site by COX-2 are involved in angiogenesis for the establishment of placenta. In the ovariectomized mice, the COX-1 gene was induced in the epithelium by a combined treatment with P4 and E2. However, P4 and/or E2 treatments failed to influence the uterine COX-2 gene. Overall, the results suggest that the uterine COX-1 gene is influenced by ovarian steroids, while the COX-2 gene is regulated by the implanting blastocyst during early pregnancy.

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I Robertshaw, F Bian, and S K Das

Adherence of an embryo to the uterus represents the most critical step of the reproductive process. Implantation is a synchronized event between the blastocyst and the uterine luminal epithelium, leading to structural and functional changes for further embryonic growth and development. The milieu comprising the complex process of implantation is mediated by estrogen through diverse but interdependent signaling pathways. Mouse models have demonstrated the relevance of the expression of estrogen-modulated paracrine factors to uterine receptivity and implantation window. More importantly, some factors seem to serve as molecular links between different estrogen pathways, promoting cell growth, acting as molecular chaperones, or amplifying estrogenic effects. Abnormal expression of these factors can lead to implantation failure and infertility. This review provides an overview of several well-characterized signaling pathways that elucidates the molecular cross talk involved in the uterus during early pregnancy.

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S K Das, H Lim, J Wang, B C Paria, M BazDresch, and S K Dey


In the mouse, the initiation of the attachment reaction between the blastocyst trophectoderm and luminal epithelium of the receptive uterus occurs in the evening (2200-2300 h) of day 4 of pregnancy (day 1=vaginal plug) and is followed by proliferation and differentiation of stromal cells into decidual cells at the sites of blastocyst attachment. This investigation demonstrates that an inappropriate expression of the human transforming growth factor α (hTGF-α) transgene in the uterus under the direction of a mouse metallothionein-I promoter downregulates uterine expression of TGF-β receptor subtypes and delays the initiation of implantation (attachment reaction) resulting in delayed parturition. This delay in the attachment reaction is accompanied by deferred uterine expression of amphiregulin. The results suggest that a coordinated 'cross-talk' between the signaling pathways executed by epidermal growth factor-like growth factors and TGF-βs is important for the normal implantation process.