ArticleProceedings of the National Academy of Sciences of the United States of America2020
A hypoxia-induced Rab pathway regulates embryo implantation by controlled trafficking of secretory granules.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 45 citations in OpenAlex.
- Deciphering the maternal uterine signals that shape placenta development.Reproduction (Cambridge, England) · 2026Review
- Real-time intrauterine dissolved oxygen dynamics across the luteal phase: a potential non-invasive functional biomarker of endometrial status.Reproductive biology and endocrinology : RB&E · 2026Observational
- Divergent Roles of HIF-1α and HIF-2α in Embryonic Development and Early Pregnancy.International journal of molecular sciences · 2026Review
- The Therapeutic Potential of Lactobacillus crispatus for Chronic Endometritis: A Comprehensive Clinical Trial and Experimental Investigation.Probiotics and antimicrobial proteins · 2025Article
- Identified endoplasmic reticulum stress-related molecular cluster and immune characterization in endometriosis.Scientific reports · 2025Article
- Hypoxia-driven circ-TBC1D1/miR-520h/EPHB4 impairs trophoblast function in unexplained recurrent spontaneous abortion.Scientific reports · 2025Article
- Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Phthalates Impair Estrogenic Regulation of HIF2α and Extracellular Vesicle Secretion by Human Endometrial Stromal Cells.Endocrinology · 2025Article
- Limiting Premenstrual Endometrial Hypoxia Inducible Factor 2 Alpha May Fine-Tune Endometrial Function at Menstruation.The Journal of clinical endocrinology and metabolism · 2025Article
- Endometrial zinc transporterPNAS nexus · 2025Article
- Linking the Warburg effect to endometrial receptivity: metabolic parallels in embryo implantation.Frontiers in cell and developmental biology · 2025Review
- Site-specific genetic and functional signatures of aortic endothelial cells at aneurysm predilection sites in healthy and AngII ApoEAngiogenesis · 2024Article
- Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression.Nucleic acids research · 2024Article
- Transplantation of human endometrial perivascular stem cells with hydroxy saffron yellow A promotes uterine repair in rats.Stem cell research & therapy · 2024Article
- Role of Endometrial Extracellular Vesicles in Mediating Cell-to-Cell Communication in the Uterus: A Review.Cells · 2023Review
- Exposure to di-isononyl phthalate during early pregnancy disrupts decidual angiogenesis and placental development in mice.Reproductive toxicology (Elmsford, N.Y.) · 2023Article
- Uterine-specificiScience · 2023Article
- Runx1 regulates critical factors that control uterine angiogenesis and trophoblast differentiation during placental development.PNAS nexus · 2023Article
- Uterine luminal-derived extracellular vesicles: potential nanomaterials to improve embryo implantation.Journal of nanobiotechnology · 2023Article
- Extracellular Vesicles Secreted by Mouse Decidual Cells Carry Critical Information for the Establishment of Pregnancy.Endocrinology · 2022Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP-9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy.
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