A hypoxia-induced Rab pathway regulates embryo implantation by controlled trafficking of secretory granules

被引:24
作者
Bhurke, Arpita [1 ]
Kannan, Athilakshmi [1 ]
Neff, Alison [2 ]
Ma, Qiuyan [2 ]
Laws, Mary J. [1 ]
Taylor, Robert N. [3 ]
Bagchi, Milan K. [2 ]
Bagchi, Indrani C. [1 ]
机构
[1] Univ Illinois, Dept Comparat Biosci, Urbana, IL 61802 USA
[2] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA
[3] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA
关键词
endometrium; implantation; hypoxia; granules; RAB; MATRIX METALLOPROTEINASES; MOUSE UTERUS; HUMAN ENDOMETRIAL; TETRASPANIN CD63; EXPRESSION; OXYGEN; CELLS; DECIDUALIZATION; PROGESTERONE; MECHANISMS;
D O I
10.1073/pnas.2000810117
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Implantation is initiated when an embryo attaches to the uterine lumina! epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2 alpha), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2 alpha expression. Further studies revealed that HIF2 alpha regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP-9 from the stroma to the epithelium to promote lumina! epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2 alpha-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy.
引用
收藏
页码:14532 / 14542
页数:11
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