Abstract
Decidualization of human endometrial stroma and gland development is mediated through cyclic AMP (cAMP), but the role of intracellular calcium ion (Ca2+) on cAMP mediated-signaling in human endometrial stroma and glandular epithelia has not been well-characterized. The present study was designed to investigate the role of intracellular Ca2+ on cAMP mediated-decidualization and gland maturation events, which can be identified by the up-regulation of prolactin and IGF-binding protein (IGFBP)1 in human endometrial stromal cells (ESCs), and cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) and glandular epithelial EM-1 cells. Increases in decidual prolactin and IGFBP-1 transcript levels, induced by cAMP-elevating agents forskolin or dibutyryl cyclic AMP, were inhibited by Ca2+ influx into ESCs with Ca2+ ionophores (alamethicin, ionomycin) in a dose-dependent manner. Conversely, inhibitors of Ca2+ influx through L-type voltage-dependent Ca2+ channel (VDCC), nifedipine and verapamil, enhanced the decidual gene expression. Furthermore, dantrolene, an inhibitor of Ca2+ release from the intracellular Ca2+ store, up-regulated prolactin and IGFBP-1 expression. Ca2+ ionophores decreased intracellular cAMP concentrations, whereas nifedipine, verapamil or dantrolene increased cAMP concentrations in ESCs. In glandular epithelial cells, similar responses in COX2 expression and PGE2 production were found when intracellular cAMP levels were up-regulated by decreases in Ca2+ concentrations. Thus, a marked decrease in cytosolic Ca2+ levels caused the elevation of cAMP concentrations, resulting in enhanced expression of implantation-related factors including decidual markers. These findings suggest that fluctuation in cytosolic Ca2+ concentrations alters intracellular cAMP levels, which then regulate differentiation of endometrial stromal and glandular epithelial cells.
Highlights
Receptive endometrium for implantation is constituted with the luminal epithelium, decidual cells, and glandular epithelial cells which secrete substances that support blastocyst development
To investigate whether Ca2+ influx into the cytoplasm affected decidual marker expression, endometrial stromal cells (ESCs) were pretreated with alamethicin or ionomycin that transports Ca2+ across the lipid bilayer of cell membrane, and were stimulated with a general activator of adenylyl cyclase (AC), forskolin or db-cyclic AMP (cAMP)
Significant decreases in prolactin and IGFBP1 were obtained at 1 μM alamethcin and 0.5 or 1 μM alamethicin, respectively. (Fig 1A and 1B)
Summary
Receptive endometrium for implantation is constituted with the luminal epithelium, decidual cells, and glandular epithelial cells which secrete substances that support blastocyst development. Decidualization of ESCs is mainly induced by ovarian steroids [5, 6], and progesterone-dependent decidualization is mediated in part by the second messenger cAMP [7, 8] This process is enhanced by physiological factors modulating adenylyl cyclase (AC) activity through receptors functionally coupled with Gs proteins such as prostaglandin (PG) E2 [9] and relaxin [10], or by a cAMP analog [5]. It has been documented that decidualization is mainly regulated by both protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC) signalings [11,12,13] These data reveal that cAMP is a key mediator of decidualization in ESCs. In addition, endometrial glandular epithelial cells synthesize and secrete implantation-related factors including PGE2 during the implantation window, which are essential for embryo development and endometrial stromal cell differentiation [14, 15]. It has been demonstrated that both cAMP/PKA and cAMP/EPAC signaling control the function of endometrial glandular cells [17]
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