title: Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus.
abstract: The optimal decidualization of endometrial stromal cells (ESCs) following embryo implantation is one of the critical steps to establish pregnancy in rodents and humans. This step is intricately regulated by ovarian hormones. Using in vitro human ESCs model, we previously showed that activation of a cAMP mediator, exchange protein directly activated by cAMP (EPAC), promotes ovarian steroid- or cAMP analog-induced decidualization. However, expressions and functions of EPAC and RAP1 in the uterus during pregnancy have not yet been examined. In this study, we found that the expression of EPAC2 and RAP1 was markedly upregulated in the decidual cells at the implantation sites on days 7 and 9 of pregnancy in rats. Furthermore, both delayed-implantation and artificial decidualization models showed that EPAC2 and RAP1 expression was enhanced in decidual cells. Significant activation of cAMP-responsive element-binding protein (CREB), a central transcriptional factor of cAMP signaling, was observed in decidual cells. These spatiotemporal expressions of protein related EPAC pathway are overlapped by sites with activated cAMP signaling, indicating the association of EPAC signaling with decidualization. Strikingly, further studies in in vitro rat decidualization model showed that the cAMP analog and medroxyprogesterone stimulated the expression of decidual markers, while knockdown of EPAC1/2 and RAP1 attenuated the expressions of these markers. Together, these findings suggest that EPAC and RAP1 are the crucial factors for endometrial decidualization in rat pregnancy.
authors.affiliation: Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kusama
authors.affiliation: Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA yoshie@toyaku.ac.jp hiro@toyaku.ac.jp.
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Yoshie
authors.affiliation: Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA yoshie@toyaku.ac.jp hiro@toyaku.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.
authors.forename: Takiko
authors.initials: T
authors.lastname: Daikoku
authors.affiliation: Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takarada
authors.affiliation: Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tachikawa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003656:Decidua / Q000378:metabolism*; D033301:Deciduoma / Q000378:metabolism; D010064:Embryo Implantation; D010065:Embryo Implantation, Delayed; D005260:Female; D005865:Gestational Age; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; C531571:Rapgef4 protein, rat; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins