TY - JOUR
T1 - HIF2a in the uterine stroma permits embryo invasion and luminal epithelium detachment
AU - Matsumoto, Leona
AU - Hirota, Yasushi
AU - Saito-Fujita, Tomoko
AU - Takeda, Norihiko
AU - Tanaka, Tomoki
AU - Hiraoka, Takehiro
AU - Akaeda, Shun
AU - Fujita, Hidetoshi
AU - Shimizu-Hirota, Ryoko
AU - Igaue, Shota
AU - Matsuo, Mitsunori
AU - Haraguchi, Hirofumi
AU - Saito-Kanatani, Mayuko
AU - Fujii, Tomoyuki
AU - Osuga, Yutaka
N1 - Funding Information:
We thank Ken-ichi Yagami (University of Tsukuba) and RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan, for providing R26GRR mice, Sudhansu K. Dey (Cincinnati Children’s Hospital Medical Center) for providing Ltf-Cre mice and reviewing the manuscript critically, Richard Behringer (The University of Texas MD Anderson Cancer Center) for providing Amhr2-Cre mice, Francesco J. DeMayo (National Institute of Environmental Health Sciences) for providing Pgr-Cre mice, Eiichi Hondo (Nagoya University) for providing the LIF expression vector, and Katie A. Gerhardt (Cincinnati Children’s Hospital Medical Center) for efficient editing of the manuscript. This work was supported by grants from the Japan Agency for Medical Research and Development (AMED) PRIME (JP18gm5910010), the Japan Society for the Promotion of Science, KAKENHI (16H04679, 16K15701, 16K15700, 16H05469, 15K10660, 15H04979, 17K16833, 17H06640, 15K15596, 16K10668), and the Takeda Science Foundation.
Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/7/2
Y1 - 2018/7/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI98931
DO - 10.1172/JCI98931
M3 - Article
C2 - 29911998
AN - SCOPUS:85049828693
SN - 0021-9738
VL - 128
SP - 3186
EP - 3197
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -