HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment
Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Norihiko Takeda, Tomoki Tanaka, Takehiro Hiraoka, Shun Akaeda, Hidetoshi Fujita, Ryoko Shimizu-Hirota, Shota Igaue, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Tomoyuki Fujii, Yutaka Osuga
Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Norihiko Takeda, Tomoki Tanaka, Takehiro Hiraoka, Shun Akaeda, Hidetoshi Fujita, Ryoko Shimizu-Hirota, Shota Igaue, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Tomoyuki Fujii, Yutaka Osuga
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Research Article Development Reproductive biology

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.

Authors

Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Norihiko Takeda, Tomoki Tanaka, Takehiro Hiraoka, Shun Akaeda, Hidetoshi Fujita, Ryoko Shimizu-Hirota, Shota Igaue, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Tomoyuki Fujii, Yutaka Osuga

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Figure 5

Uterine HIF2α places the implanting embryo in the bottom of the endometrial crypt through induction of LIF.

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Uterine HIF2α places the implanting embryo in the bottom of the endometr...
(A) The positioning of embryo attachment at the bottom of the endometrial crypt was impaired in Hif2a-uKO mice at 1000 hours on day 5. Scale bar, 100 μm; arrowhead, an embryo; s, stroma; le, luminal epithelium. (B and C) COX2, a marker of embryo attachment reaction, was similarly expressed in the implantation sites of both Hif2a-uKO and control mice. P > 0.05, n ≥ 5, mean ± SEM, Student’s t test. (D) The expression of LIF, a key regulator of embryo attachment, was decreased at the implantation site of Hif2a-uKO mice on day 5 morning. *P < 0.05, n ≥ 5, mean ± SEM, Student’s t test. (E) Activation of STAT3, a downstream signaling of LIF, was eliminated in the implantation site of Hif2a-uKO mice, as demonstrated by phosphorylated STAT3 immunostaining. (F) Intraperitoneal injection of recombinant LIF (20 μg/mouse on day 4) into Hif2a-uKO mice in addition to P4 injection normalized the position of embryo attachment to the bottom of the endometrial crypt on day 5 morning. (G) LIF administration could not rescue implantation failure in Hif2a-uKO mice on day 6 morning (arrow, a destroyed embryo with blood cell infiltration).