Regulatory Action of Calcium Ion on Cyclic AMP-Enhanced Expression of Implantation-Related Factors in Human Endometrial Cells

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.

S100 protein family and embryo implantation

“…Ishikawa cells culture with implantation‐related hormones like E2, E 2+ P4, P4, and hCG in the in vitro environment, no significant changes were made in the expression of S100a11 and its protein but treat of the cells with EGF significantly increased protein levels and mRNA S100A11. Therefore, it can be concluded that the expression of S100A11 is controlled by EGF …”

“…S100A10 silencing inhibits prolactin secretion in human embryonic stem cells. But significantly increases prolactin in human endometrial epithelial cells and still the molecular mechanism that S100A10 defection caused by it on different expressions of prolactin, not thoroughly known …”

Changes in calcium levels in the endometrium throughout pregnancy and the role of calcium on endometrial gene expression at the time of conceptus implantation in pigs

“…Because endometrial calcium secretion into the uterine lumen and endometrial expression of TRPV6 increase on Day 12 of pregnancy, as shown in Figure , and calcium entry into human endometrial epithelial cells changes the expression of implantation‐related genes (Kusama et al, ; Tinel et al, ), we hypothesized that endometrial calcium might affect the expression of genes involved in conceptus implantation, calcium ion regulation, and PG metabolism and transport in the porcine endometrium. Thus, we chose to evaluate expression levels of several genes with well‐known roles in conceptus implantation, calcium ion regulation, and PG metabolism and transport in the porcine endometrium.…”

“…Calcium entry into human endometrial epithelial cells increases adhesiveness to trophoblast cells in vitro (Tinel et al, ), and intracellular calcium ion concentration regulates the expression of implantation‐related genes in human endometrial epithelial and stromal cells (Kusama et al, ), suggesting the important role of calcium in mediating embryo implantation by affecting endometrial gene expression. We hypothesized that increasing calcium entry would affect endometrial gene expression during the implantation period in pigs.…”

Human S100A10 plays a crucial role in the acquisition of the endometrial receptivity phenotype

“…As for decidualisation, uterine gland maturation is mediated through cAMP allowing expression of implantation-related factors including decidual markers. 32,33 Decidualization has been widely investigated using in vitro culture models of stromal endometrial cells. 34 However, the behavior of epithelial endometrial cells during the decidualization process of stromal cells has rarely been studied.…”