| RRC ID |
53172
|
| 著者 |
Matsumoto L, Hirota Y, Saito-Fujita T, Takeda N, Tanaka T, Hiraoka T, Akaeda S, Fujita H, Shimizu-Hirota R, Igaue S, Matsuo M, Haraguchi H, Saito-Kanatani M, Fujii T, Osuga Y.
|
| タイトル |
HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment.
|
| ジャーナル |
J Clin Invest
|
| 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.
|
| 巻・号 |
128(7)
|
| ページ |
3186-3197
|
| 公開日 |
2018-7-2
|
| DOI |
10.1172/JCI98931
|
| PII |
98931
|
| PMID |
29911998
|
| PMC |
PMC6025968
|
| MeSH |
Animals
Basic Helix-Loop-Helix Transcription Factors / deficiency
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / physiology*
Blastocyst / physiology
Decidua / drug effects
Decidua / physiology
Disease Models, Animal
Embryo Implantation / physiology*
Epithelium / physiology
Female
Fertility / physiology
Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / physiology
Infertility, Female / etiology
Infertility, Female / pathology
Infertility, Female / physiopathology
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Mice, Transgenic
Pregnancy
Progesterone / administration & dosage
Signal Transduction
Uterus / physiology*
|
| IF |
11.864
|
| 引用数 |
8
|
| リソース情報 |
| 実験動物マウス |
RBRC04874 |
