Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (Epac)

Kazuya Kusama, K Kusama, M Yoshie, Mikihiro Yoshie, K Tamura, Kazuhiro Tamura, Y Kodaka, Yasuhiro Kodaka, A Hirata, Akihiko Hirata, Toshihiro Sakurai, T Sakurai, H Bai, Hanako Bai, K Imakawa, Kazuhiko Imakawa, Hirotaka Nishi, H Nishi, K Isaka, Keiichi Isaka, Takeshi Nagai, T Nagai, Toshitaka Nagao, T Nagao, E Tachikawa, Eiichi Tachikawa
Placenta · 2013 · vol. 34(3) , pp. 212–221 · doi:10.1016/j.placenta.2012.12.017 · PMID:23352189 · W1987250056
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This study investigated the role of Epac in regulating decidualization within human endometrial stromal cells and identified its specific contribution to this process.

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Abstract

INTRODUCTION: Human endometrial stromal cells (ESCs) undergo differentiation during the decidualization process. Decidualization is characterized by their enhanced production of IGF binding protein-1 (IGFBP-1), prolactin (PRL), and the forkhead transcriptional factor FOXO1, and transformation into more rounded cells, during the secretory phase of the menstrual cycle and subsequent pregnancy. Protein kinase A (PKA)-mediated cAMP signaling is crucial for this process. The present study was undertaken to examine the involvement of a mediator of cAMP signaling, exchange protein directly activated by cAMP (Epac), in decidualization of cultured ESCs. RESULTS: Treatment of ESCs with the Epac-selective cAMP analog 8-CPT-2-OMe-cAMP (CPT) had no effect on IGFBP-1, PRL, and FOXO1 mRNA expression. However, CPT potentiated IGFBP-1 and PRL expression stimulated by the PKA-selective cAMP analog N(6)-Phe-cAMP (Phe) and activated Rap1, a downstream regulator of Epac signaling. Knock-down of Epac1, Epac2, or Rap1 significantly inhibited the Phe- or Phe/CPT-induced increase in IGFBP-1 and PRL expression, as well as Rap1 activation. Furthermore, CPT enhanced IGFBP-1 and PRL expression and the morphological differentiation induced by ovarian steroids, whereas Epac1, Epac2, or Rap1 knock-down suppressed these events. CONCLUSION: These data provide evidence for the involvement of the Epac/Rap1 signaling pathway in cAMP-mediated decidualization of human ESCs.

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MeSH descriptors

Decidua Decidua Guanine Nucleotide Exchange Factors Stromal Cells Cell Differentiation Cells, Cultured Cyclic AMP Cyclic AMP Cyclic AMP Decidua Decidua Endometrium Endometrium Endometrium Endometrium Female Forkhead Box Protein O1 Forkhead Transcription Factors Forkhead Transcription Factors Forkhead Transcription Factors

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