Maternal–fetal mechanisms underlying adaptation to hypoxia during early pregnancy.

Embryo implantation and processes of early pregnancy occur in a low-oxygen tissue environment controlled by hypoxia-inducible transcription factors of the hypoxia inducible factor (Hif) family. Hif2α has emerged as a pivotal factor in mediating uterine adaptation to hypoxia during early pregnancy. In mice, endometrial stromal Hif2α regulates the expression of the vesicular trafficking protein Rab27b, which in turn controls the release of both secretory granules and extracellular vesicles (EVs). These EVs harbor a variety of cargoes that control essential functional steps during pregnancy. In both mice and humans, EVs secreted by decidualizing stromal cells are taken up by stromal, endothelial, and trophoblast cells to support decidualization, blood vessel formation, and trophoblast development in the uterine milieu during early pregnancy. In mice, embryonic Hifs are essential for placental development. In humans, Hifs intrinsic to the trophoblast precursor cells are critical for their differentiation to the extravillous trophoblast (EVT) lineage. During the process of implantation, the embryo first attaches to the uterine epithelium and then invades the underlying stroma, resulting in the transformation of the stroma into a secretory tissue that surrounds the embryo. An intricate dialogue allows the developing embryo and the maternal tissue to be in constant communication with each other. In many mammals, including humans, embryo implantation and early pregnancy events take place in a low-oxygen environment regulated by hypoxia-inducible transcription factors. The mechanisms by which maternal and embryonic tissue compartments adapt to hypoxia are essential for the success of pregnancy outcomes. In this review we highlight recent work describing signaling pathways that operate in the hypoxic uterus to facilitate embryo implantation and promote the successful establishment of pregnancy. [ABSTRACT FROM AUTHOR]