Review: Oxygen and trophoblast biology – A source of controversy

Abstract

Oxygen is necessary for life yet too much or too little oxygen is toxic to cells. The oxygen tension in the maternal plasma bathing placental villi is <20 mm Hg until 10–12 weeks’ gestation, rising to 40–80 mmHg and remaining in this range throughout the second and third trimesters. Maldevelopment of the maternal spiral arteries in the first trimester predisposes to placental dysfunction and sub-optimal pregnancy outcomes in the second half of pregnancy. Although low oxygen at the site of early placental development is the norm, controversy is intense when investigators interpret how defective transformation of spiral arteries leads to placental dysfunction during the second and third trimesters. Moreover, debate rages as to what oxygen concentrations should be considered normal and abnormal for use in vitro to model villous responses in vivo. The placenta may be injured in the second half of pregnancy by hypoxia, but recent evidence shows that ischemia with reoxygenation and mechanical damage due to high flow contributes to the placental dysfunction of diverse pregnancy disorders. We overview normal and pathologic development of the placenta, consider variables that influence experiments in vitro, and discuss the hotly debated question of what in vitro oxygen percentage reflects the normal and abnormal oxygen concentrations that occur in vivo. We then describe our studies that show cultured villous trophoblasts undergo apoptosis and autophagy with phenotype-related differences in response to hypoxia.

Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions

“…A number of reports have demonstrated that trophoblast cells respond to oxygen restriction (reviewed in ref. 34). In vitro experimentation has yielded a range of responses, some of which are contradictory, but, again, methodological differences are the likely cause for the discrepancies.…”

Autophagy Induced by Tumor Necrosis Factor α Mediates Intrinsic Apoptosis in Trophoblastic Cells

“…1,2 In contrast, increased trophoblastic apoptosis has been reported in pregnancies complicated by fetal growth restriction (FGR) or preeclampsia (PE), [3][4][5] suggesting that altered regulation of trophoblastic apoptosis may contribute to the pathophysiology of FGR or PE. 6 Autophagy has been implicated in pathophysiologic processes including cellular differentiation, cancer, metabolic or neurodegenerative diseases, and cell death. 7,8 However, autophagic function in the human placenta is not fully understood.…”

Oxidative stress in pregnancy and fertility pathologies

“…In the first trimester, placental O 2 levels are relatively low, with a pressure around 20 mmHg (Tuuli et al 2011), due to lack of established maternal intraplacental circulation, which is believed to be the reason why the embryo is particularly protected from ROS at that time. These low O 2 levels are essential for normal cell proliferation and placental angiogenesis, promoted by hypoxia-induced transcriptional and posttranscriptional regulation of angiogenic factors such as vascular endothelial growth factor and placental growth factor (Tuuli et al 2011). However, once maternal intraplacental circulation is fully established (toward the end of the first trimester), the O 2 tension triples and, with it, so does ROS levels, particularly at the syncytiotrophoblastic layer (Burton and Jauniaux 2011;Burton et al 2010).…”

“…However, once maternal intraplacental circulation is fully established (toward the end of the first trimester), the O 2 tension triples and, with it, so does ROS levels, particularly at the syncytiotrophoblastic layer (Burton and Jauniaux 2011;Burton et al 2010). The placenta then adapts to this increase by modulating hypoxia-inducible factor 1α (HIF-1α) and increasing cellular antioxidant levels (Tuuli et al 2011). Under normal conditions, this adaptation is favorable to fetal development.…”

“…However, in a scenario where oxidative stress is abnormally increased, damage affecting both the mother and the fetus can be observed. Several studies have been conducted for the last two decades that relate increased oxidative stress levels to several pregnancy pathologies, including gestational diabetes mellitus, spontaneous abortion, idiopathic recurrent pregnancy loss, defective embryogenesis, drug-induced teratogenicity, preeclampsia, intrauterine growth restriction, and minor congenital abnormalities, as well as to future diseases in adulthood such as obesity, diabetes mellitus, and hypertension (Burton et al 2009(Burton et al , 2010Dröge 2002;Hempstock et al 2003;Myatt 2010;Poston et al 2011;Shibata et al 2010;Theuerkauf et al 2010;Tuuli et al 2011).…”