Different Regulatory Pathways of Endometrial Connexin Expression: Preimplantation Hormonal-Mediated Pathway Versus Embryo Implantation-Initiated Pathway1

Abstract

Transformation of the endometrium into the receptive phase is under the control of ovarian steroid hormones and is modulated by embryonic signals during implantation. We have previously shown that this differentiation process is accompanied by a suppression of gap junction connexins (Cx) 26 and 43 before implantation followed by a local induction of both connexins in the implantation chamber. In the present study, we demonstrate that connexin gene expression in the rodent endometrium is regulated via two distinct signaling pathways during these different stages of early pregnancy. During preimplantation, transcription of connexins can be induced by estrogen via an estrogen receptor (ER)-dependent pathway. Additionally, Cx26 and Cx43 are induced by embryonic signals during implantation and delayed implantation as well as during artificially induced decidualization. In contrast to the estrogen-induced expression, this embryonic/decidual-associated induction of Cx26 and Cx43 could not be blocked by antiestrogen, thus pointing to another regulatory pathway independent of the ER. Studies in ERalpha and ERbeta knockout mice confirmed these different pathways, demonstrating that in the endometrium, estrogen-mediated Cx26 gene induction, but not induction during decidualization, is dependent on functional ERalpha. To evaluate potential embryonic signals regulating Cx26 expression, uteri of pseudopregnant animals were incubated with different mediators in an organ-culture model, showing that catechol estrogen and mediators of the inflammatory cascade such as prostaglandin F(2alpha) and interleukin-1beta are able to induce Cx26 expression through the ER-independent pathway. Thus, the present study demonstrates that endometrial expression of Cx26 and Cx43 is induced via estrogen and ERalpha during preimplantation but then utilizes an ER-independent signaling pathway during embryo implantation and decidualization.

De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis

“…Recently we have shown that conditional loss of expression of Cx43, a major gap junction component in uterine stromal cells, impairs decidualization and angiogenesis during early pregnancy (6). The uterine expression of Cx43 is regulated by E (22). It is therefore conceivable that the local E produced by the aromatase in the decidua controls Cx43 expression, which in turn contributes to the progression of Fig.…”

Label-Retaining Stromal Cells in Mouse Endometrium Awaken for Expansion and Repair After Parturition

“…used implantation marker in murine models and localized distinctively in implantation/placental loci [27][28][29][30], this marker was used to assess the spatial distribution of LRSC during gestation (GD7, 14) and the early postpartum (PPD1) period. The connexin 43 expression was restricted to the implantation/ placental loci of the gestational endometrium (Fig.…”

Connexins: Key Mediators of Endocrine Function

“…Implantation of mammalian embryos in the uterus occurs in the so-called receptive phase, during which steroid hormones and local embryonic signals suppress the expression of endometrial Cx26 and Cx43. Later, connexin expression is locally reinduced by the implanting blastocyst, presumably as a result of factors secreted by the growing throphoblast (184,185,186). Ovariectomized rats treated with different ratios of 17␤-estradiol and progesterone revealed a dose-and timedependent regulation of the expression of Cx26 (the main connexin of the endometrial epithelium) and Cx43 (the prominent connexin of uterine stroma and myometrium) but not Cx32, indicating that hormonal ratios mimicking pregnancy conditions differentially regulate ␣-and ␤-type connexins (185).…”

“…During preimplantation, this induction is due to estrogens, via the activation of a pathway initiated at ␣-estrogen receptors. However, during the subsequent embryo implantation and decidualization, endometrial connexins are upregulated by an estrogen receptor-independent pathway, possibly implicating catechol estrogen, prostaglandin F 2␣ , and interleukin-1␤ (184). LH and follicle-stimulating hormone control the coupling of ovarian thecal cells, by regulating Cx43 expression at the transcriptional, translational, and posttranslational levels (178).…”