Autotaxin–lysophosphatidic acid– LPA ₃ signaling at the embryo‐epithelial boundary controls decidualization pathways

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 LPA 3 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 LPA 3 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–LPA 3 signaling at the embryo‐epithelial boundary induces decidualization via the canonical HB‐EGF and COX‐2 pathways.

Administration of Herb Formulation Enhanced Blastocyst Implantation via Iκb Activation in Mouse Endometrium

“…Decidualization is a series of changes in uterus during the early stages of pregnancy that are necessary for placenta formation and fetal development [46][47][48]. Decidualization occurs only near the embryos in mice, whereas this process occurs periodically, regardless of the presence or absence of an embryo in humans [49].…”

“…Decidualization occurs only near the embryos in mice, whereas this process occurs periodically, regardless of the presence or absence of an embryo in humans [49]. During decidualization, uterine epithelium falls apart and is followed by extensive proliferation and angiogenesis in the subepithelial stroma [46]. The signal transduction required for successful decidualization is generated by two types of cell-cell interactions: embryo-epithelial and epithelial-stromal [46].…”

“…During decidualization, uterine epithelium falls apart and is followed by extensive proliferation and angiogenesis in the subepithelial stroma [46]. The signal transduction required for successful decidualization is generated by two types of cell-cell interactions: embryo-epithelial and epithelial-stromal [46]. COX-2 and epidermal growth factor (EGF) family members including heparin binding-EGF (HB-EGF) are activated in luminal epithelium surrounding blastocyst and induce activation of Bmp2 (bone morphogenic protein 2) and Wnt4 (wingless-related mouse mammary tumor virus integration site 4) resulting in stromal cell growth [46,50].…”

The ameliorating effects of Bushen Tiaoxue Granules and Kunling Wan on impaired angiogenesis and endometrial receptivity in rats following controlled ovarian hyperstimulation

“…19,42 LPA3 signaling is highly dependent on female sex hormones, P4 and E2. 43 In order to explore the expression of LPA3 after COH and the effect of BTG and KW, immunofluorescence staining and Western blot were conducted. As shown in Figure 9A, the expression of LPA3 was decreased in the cytoplasm of endometrial luminal, glandular, and stroma epitheliums after COH compared with the Control group, which was enhanced by pre-treatment with BTG and KW, respectively.…”

Ubiquitin‐specific protease 7 (USP7) is essential for endometrial stromal cell decidualization in mice

“…Infertility is a global problem experienced by about 10%–15% of couples during their reproductive years. Other than the high cost associated with the use of assisted reproductive technology (ART), the pregnancy success rate is low (Aikawa et al., ) (Cha, Sun, & Dey, ). These pregnancy failures are believed to be primarily due to defects in early pregnancy events including implantation and decidualization (Lim & Wang, ).…”