RRC ID 53172
Author Matsumoto L, Hirota Y, Saito-Fujita T, Takeda N, Tanaka T, Hiraoka T, Akaeda S, Fujita H, Shimizu-Hirota R, Igaue S, Matsuo M, Haraguchi H, Saito-Kanatani M, Fujii T, Osuga Y.
Title HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment.
Journal J Clin Invest
Abstract Although it has been reported that hypoxia inducible factor 2 α (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2α in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2α regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2α allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.
Volume 128(7)
Pages 3186-3197
Published 2018-7-2
DOI 10.1172/JCI98931
PII 98931
PMID 29911998
PMC PMC6025968
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / deficiency Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / physiology* Blastocyst / physiology Decidua / drug effects Decidua / physiology Disease Models, Animal Embryo Implantation / physiology* Epithelium / physiology Female Fertility / physiology Hypoxia-Inducible Factor 1, alpha Subunit / deficiency Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / physiology Infertility, Female / etiology Infertility, Female / pathology Infertility, Female / physiopathology Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Knockout Mice, Transgenic Pregnancy Progesterone / administration & dosage Signal Transduction Uterus / physiology*
IF 11.864
Times Cited 8
Mice RBRC04874