HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment

Although it has been reported that hypoxia inducible factor 2 alpha (Hif2 alpha), 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 Hif2 alpha in the whole uterus (Hif2 alpha-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P-4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2 alpha-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2 alpha-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 Hif2 alpha (Hif2 alpha-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2 alpha (Hif2 alpha-sKO mice) showed normal fertility, suggesting the importance of stromal HIF2 alpha in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2 alpha-uKO stroma at the attachment site, suggesting that stromal HIF2 alpha regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2 alpha allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.