Maternal spiral arteries and newly formed decidual capillaries support embryonic development prior to placentation. Previous studies demonstrated that Notch signaling is active in endothelial cells of both decidual capillaries and spiral arteries, however the role of Notch signaling in physiologic decidual angiogenesis and maintenance of the decidual vasculature in early mouse pregnancy has not yet been fully elucidated. We used the Cdh5-CreERT2;Jagged1(Jag1)flox/flox (Jag1∆EC) mouse model to delete Notch ligand, Jag1, in maternal endothelial cells during post-implantation, pre-placentation mouse pregnancy. Loss of endothelial Jag1 leads to increased expression of Notch effectors, Hey2 and Nrarp, and increased endothelial Notch signaling activity in areas of the decidua with remodeling angiogenesis. This correlated with an increase in Dll4 expression in capillary endothelial cells, but not spiral artery endothelial cells. Consistent with increased Dll4/Notch signaling, we observed decreased VEGFR2 expression and endothelial cell proliferation in angiogenic decidual capillaries. Despite aberrant Dll4 expression and Notch activation in Jag1∆EC mutants, pregnancies were maintained and the decidual vasculature was not altered up to embryonic day 7.5. Thus, Jag1 functions in the newly formed decidual capillaries as an antagonist of endothelial Dll4/Notch signaling during angiogenesis, but Jag1 signaling is not necessary for early uterine angiogenesis.
In the 1st trimester of human pregnancy, low oxygen tension or hypoxia, is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multuple cell types, the relationship between hypoxia and Notch in 1st trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human 1st trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a -secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed 2nd trimester chorionic villous sampling (CVS) samples and 3rd trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies, and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.
Proper development and function of the mammalian placenta requires interactions between embryo-derived trophoblasts and uterine endothelial cells to form mosaic vessels that facilitate blood flow to a developing conceptus. Notch signaling utilizes a cell–cell contact dependent mechanism to drive cell behaviors, such as differentiation and invasion. In mice, Notch2 is needed for proper placentation and embryo survival. We used transgenic mice with a dominant-negative form of Mastermind-like1 and Cyp19-Cre and Tpbpa-Cre drivers to inhibit canonical Notch signaling in trophoblasts. Both Cre drivers resulted in robust placental expression of dominant-negative Mastermind-like1. All pregnancies progressed beyond mid-gestation and morphological analyses of placentas revealed no differences between mutants and controls. Our data suggest that mouse placentation occurs normally despite dominant negative inhibition of trophoblast canonical Notch signaling and that Notch2 signaling via the canonical pathway is not necessary for placentation.
Interleukin-33 (IL-33) is an IL-1 family cytokine with pleiotropic effects on diverse cell types. Dysregulated IL-33 signaling has been implicated in pregnancy-related disorders, including preeclampsia and recurrent pregnancy loss, and in ovarian function in women undergoing controlled ovarian stimulation for in vitro fertilization. To date, expression of IL-33 and its receptor subunit, ST2, in the female reproductive tract remains poorly characterized. We identify IL-33-expressing oocytes surrounded by ST2-expressing granulosa cells at all stages of follicular development, in addition to IL-33+ and ST2+ non-endothelial cells in the ovarian stroma and theca layer in ovaries from adult mice. These expression patterns are similar in estrus- and diestrus-stage adults and in pubescent mice, suggesting a role for IL-33 signaling in ovarian function throughout development and in the estrous cycle. In the uterus, we find expression of IL-33 and ST2 in glandular and luminal epithelia during estrus and at the initiation of pregnancy. Uterine IL-33 expression was modulated by the estrous cycle and was reduced in pubescent females. Last, superovulation increases transcripts for IL-33 and the soluble form of ST2 (sST2) in ovaries, and for IL-33 in uteri. Collectively, our findings lay the foundation for studies identifying cell type-specific requirements for IL-33/ST2 signaling in the establishment and maintenance of mouse pregnancy.
This data suggest that endometrial EGFR mRNA expression varies in association with the histologic changes of the normal menstrual cycle, and may be associated with the presence of leiomyomata uteri.
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