HIF2a 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, Shota Igaue, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Tomoyuki Fujii, Yutaka Osuga

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Abstract

Although it has been reported that hypoxia inducible factor 2 a (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 HIF2a 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 HIF2a regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2a allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.

Original languageEnglish
Pages (from-to)3186-3197
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number7
DOIs
Publication statusPublished - 2018 Jul 2

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Embryonic Structures
Epithelium
Infertility
Uterus
Matrix Metalloproteinase 15
endothelial PAS domain-containing protein 1
Protein-Lysine 6-Oxidase
Adrenomedullin
Leukemia Inhibitory Factor
Trophoblasts
Metalloproteases
Blastocyst
Pregnancy Outcome
Phosphatidylinositol 3-Kinases
Vascular Endothelial Growth Factor A
Transgenic Mice
Progesterone
Fertility
Oxygen
Pregnancy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Matsumoto, L., Hirota, Y., Saito-Fujita, T., Takeda, N., Tanaka, T., Hiraoka, T., ... Osuga, Y. (2018). HIF2a in the uterine stroma permits embryo invasion and luminal epithelium detachment. Journal of Clinical Investigation, 128(7), 3186-3197. https://doi.org/10.1172/JCI98931

HIF2a in the uterine stroma permits embryo invasion and luminal epithelium detachment. / Matsumoto, Leona; Hirota, Yasushi; Saito-Fujita, Tomoko; Takeda, Norihiko; Tanaka, Tomoki; Hiraoka, Takehiro; Akaeda, Shun; Fujita, Hidetoshi; Shimizu, Ryoko; Igaue, Shota; Matsuo, Mitsunori; Haraguchi, Hirofumi; Saito-Kanatani, Mayuko; Fujii, Tomoyuki; Osuga, Yutaka.

In: Journal of Clinical Investigation, Vol. 128, No. 7, 02.07.2018, p. 3186-3197.

Research output: Contribution to journalArticle

Matsumoto, L, Hirota, Y, Saito-Fujita, T, Takeda, N, Tanaka, T, Hiraoka, T, Akaeda, S, Fujita, H, Shimizu, R, Igaue, S, Matsuo, M, Haraguchi, H, Saito-Kanatani, M, Fujii, T & Osuga, Y 2018, 'HIF2a in the uterine stroma permits embryo invasion and luminal epithelium detachment', Journal of Clinical Investigation, vol. 128, no. 7, pp. 3186-3197. https://doi.org/10.1172/JCI98931
Matsumoto L, Hirota Y, Saito-Fujita T, Takeda N, Tanaka T, Hiraoka T et al. HIF2a in the uterine stroma permits embryo invasion and luminal epithelium detachment. Journal of Clinical Investigation. 2018 Jul 2;128(7):3186-3197. https://doi.org/10.1172/JCI98931
Matsumoto, Leona ; Hirota, Yasushi ; Saito-Fujita, Tomoko ; Takeda, Norihiko ; Tanaka, Tomoki ; Hiraoka, Takehiro ; Akaeda, Shun ; Fujita, Hidetoshi ; Shimizu, Ryoko ; Igaue, Shota ; Matsuo, Mitsunori ; Haraguchi, Hirofumi ; Saito-Kanatani, Mayuko ; Fujii, Tomoyuki ; Osuga, Yutaka. / HIF2a in the uterine stroma permits embryo invasion and luminal epithelium detachment. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 7. pp. 3186-3197.
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AU - Matsumoto, Leona

AU - Hirota, Yasushi

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AU - Tanaka, Tomoki

AU - Hiraoka, Takehiro

AU - Akaeda, Shun

AU - Fujita, Hidetoshi

AU - Shimizu, Ryoko

AU - Igaue, Shota

AU - Matsuo, Mitsunori

AU - Haraguchi, Hirofumi

AU - Saito-Kanatani, Mayuko

AU - Fujii, Tomoyuki

AU - Osuga, Yutaka

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