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

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.

Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation

“…In mice, uterine HIF2α expression is intense during peri‐implantation period . We recently revealed that entire uterine deletion of HIF2α results in implantation failure due to embryo invasion failure in mice (Figure ). Supplementation of both P 4 and LIF does not rescue embryo invasion but recovers decidual growth arrest and inappropriate location of implantation site in uterine HIF2α knockout mice.…”

“…On day 5 evening, trophoblast cells enter the stromal layer of the endometrium. Thus, embryo implantation is completed …”

“…This limited duration of uterine capacity for blastocyst attachment is called as “implantation window” . The luminal epithelium at the lateral side of the embryo attachment site detaches itself from the stroma and then trophoblast starts to invade the stroma, which is called “embryo invasion” . Thus, successful implantation is controlled by uterine receptivity precisely, and uterine PDS is a major indicator of uterine receptivity.…”

“…PR antagonist RU486 injection in the peri‐implantation period hampers uterine PDS and embryo implantation in wild‐type (WT) mice . According to the previous literature, implantation failure occurs in all types of mice with impaired uterine PDS . PR has two isoforms, PR‐A and PR‐B.…”

“…Supplementation of both P 4 and LIF does not rescue embryo invasion but recovers decidual growth arrest and inappropriate location of implantation site in uterine HIF2α knockout mice. Notably, embryo invasion failure in uterine HIF2α null mice is caused by the intact alignment of luminal epithelium, which hampers direct attachment of embryo to uterine stroma, and inactivation of AKT pathway as an embryonic survival signal . Uterine stromal HIF2α knockout mice are infertile due to impaired embryo invasion, whereas uterine epithelial HIF2α knockout mice demonstrate normal fertility, indicating the critical role of uterine stromal HIF2α in embryo invasion.…”