Decreased Notch Pathway Signaling in the Endometrium of Women With Endometriosis Impairs Decidualization

Abstract

Decreased Notch signaling is associated with endometriosis and contributes to impaired decidualization through the down-regulation of FOXO1.

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

“…These studies suggest that Notch signaling plays two distinct roles during decidualization. Silencing of NOTCH1 during the initiation of decidualization inhibits stromal cell differentiation, indicating that activation of Notch1 signaling is required only at the initiation of the decidualization process, which is also associated with the induction of FOXO1 (12). As decidualization progresses, Notch1 is down-regulated (10,11), and this down-regulation is necessary to permit differentiation into the decidual phenotype, which was shown in a previous study (11) and is also shown in this study.…”

“…Our laboratory has previously reported that both the conditional deletion of Notch1 in the mouse uterus and NOTCH1 silencing in Human Uterine Fibroblasts (HuFs) inhibit decidualization (10,11). In the pathological condition of endometriosis, the decrease in NOTCH1 in eutopic endometrium results in impaired decidualization of endometrial stromal cells from patients with the disease (12). NOTCH2 has also been shown as a regulator of decidualization (13).…”

Immune mechanisms at the maternal-fetal interface: perspectives and challenges

“…Emerging evidence strongly supports the tenet that defects in uterine gland secretory functions, stromal cell decidualization and/ or uNK cell development and function are causative factors in pregnancy failure and pregnancy complications such as preeclampsia and fetal growth restriction. Moreover, women with endometriosis have higher rates of implantation failure that are associated with defects in stromal cell decidualization and phenotypic alterations of uNK cells 5,6 . An increased understanding of early pregnancy biology is fundamentally important for the diagnosis, prevention and treatment of fertility and pregnancy problems as well as fertility-associated diseases in women.…”

“…In mammalian species, the role of Notch has been studied extensively in the context of cancer biology, and Notch pathway inhibitors are being developed that target cancer stem cells. Notch1, one of four Notch receptors, mediates stromal cell survival during decidualization, and the absence of Notch1 results in decreased cell proliferation, increased apoptosis and impaired decidualization in the context of endometriosis 5 . To further evaluate the role of all Notch receptors in the context of endometrial biology, Asgerally Fazleabas and co-workers at Michigan State University inhibited all canonical Notch signaling by generating a uterine-specific deletion of Rbpj , the nuclear transducer of Notch signaling, in mice.…”

Implantation and Establishment of Pregnancy in Human and Nonhuman Primates

“…Subsequently the decrease in CG signaling appears to be necessary for the completion of decidualization. Our recent studies demonstrated that NOTCH1, a membrane receptor of Notch signaling, may mediate CG-regulated decidualization (Afshar et al 2012; Su et al 2015). …”