| Affiliation: | 1. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan;2. Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama, Japan;3. Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED‐CREST), Chiyoda‐ku, Tokyo, Japan;4. Department of Integrative Genomics, Tohoku Medical Megabank, Tohoku University, Sendai, Miyagi, Japan;5. Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan;6. Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;7. Tokyo Metropolitan Institute of Medical Science, Setagaya‐ku, Tokyo, Japan;8. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan;9. RIKEN, Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan;10. Graduate School of Pharmaceutical Sciences, Keio University, Minato‐ku, Tokyo, Japan;11. Department of Clinical Laboratory, The University of Tokyo Hospital, Bunkyo‐ku, Tokyo, Japan;12. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA |
| Abstract: | During pregnancy, up‐regulation of heparin‐binding (HB‐) EGF and cyclooxygenase‐2 (COX‐2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G‐protein‐coupled receptor LPA3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA‐producing enzyme autotaxin (ATX) in pregnant mice leads to HB‐EGF and COX‐2 down‐regulation near embryos and attenuates decidual reactions. Conversely, selective pharmacological activation of LPA3 induces decidualization via up‐regulation of HB‐EGF and COX‐2. ATX and its substrate lysophosphatidylcholine can be detected in the uterine epithelium and in pre‐implantation‐stage embryos, respectively. Our results indicate that ATX–LPA–LPA3 signaling at the embryo‐epithelial boundary induces decidualization via the canonical HB‐EGF and COX‐2 pathways. |
