Abstract
Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.
Highlights
The placenta is a transient organ established during pregnancy to ensure proper fetal development by providing gas and nutrient exchange between the mother and fetus.Starting from the implantation of the blastocyst, cells originating from the fetus must survive under extremely harsh conditions in the maternal uterus, such as severe hypoxia, lack of vascularization, and a potential attack from the maternal immune system
One example is genes in the vascular endothelial growth factor (VEGF)-VEGFR family, whose expression is under control of hypoxia-inducible factor (HIF)-1 and whose function is related to placental angiogenesis
FurtherFurther researchresearch is needed needed to identify more downstream genes that can affect placental cells to respond to a to identify more downstream genes that can affect placental cells to respond to a hypoxic hypoxic microenvironment. These studies will improve our understanding of the effects of hypoxia on the early stages of placental development
Summary
The placenta is a transient organ established during pregnancy to ensure proper fetal development by providing gas and nutrient exchange between the mother and fetus. Both in vivo and in vitro studies have shown that in the first trimester, uNK cells and dMφs infiltrate the walls of spiral arteries and mediate the disruption of vascular smooth muscle cells, leading to dilation These events occur before invasion and relining of the vessels by EVTs. uNK cells can regulate the timing of EVT migration and the depth of EVT invasion, thereby playing a critical role in spiral artery remodeling. Different from dMφs, which are recruited from the maternal circulation, there is another homogeneous population of macrophages of fetal origin, which are called Hofbauer cells (HBCs) These cells are typically found in the endothelium and in proximity to trophoblasts, through which they regulate placental vascular development via paracrine signaling or cell-to-cell crosstalk [6,7]. They are able to respond to toll-like receptor (TLR) stimulation and are phagocytotic, suggesting that HBCs can have a defensive microbicidal capacity to prevent microbes from entering the placenta
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