Graham J Burton,Tereza Cindrova-Davies, Hong wa Yung and Eric Jauniaux
Abstract
Development of the human placenta takes place in contrasting oxygen concentrations at different stages of gestation, from ~20 mmHg during the first trimester rising to ~60 mmHg at the start of the second trimester before gradually declining to ~40 mmHg at term. In view of these changes, the early placenta has been described as ‘hypoxic’. However, placental metabolism is heavily glycolytic, supported by the rich supply of glucose from the endometrial glands, and there is no evidence of energy compromise. On the contrary, the trophoblast is highly proliferative, with the physiological low-oxygen environment promoting maintenance of stemness in progenitor populations. These conditions favour the formation of the cytotrophoblastic shell that encapsulates the conceptus and interfaces with the endometrium. Extravillous trophoblast cells on the outer surface of the shell undergo an epithelial-mesenchymal transition and acquire invasive potential. Experimental evidence suggests that these changes may be mediated by the higher oxygen concentration present within the placental bed. Interpreting in vitro data is often difficult, however, due to the use of non-physiological oxygen concentrations and trophoblast-like cell lines or explant models. Trophoblast is more vulnerable to hyperoxia or fluctuating levels of oxygen than to hypoxia, and some degree of placental oxidative stress likely occurs in all pregnancies towards term. In complications of pregnancy, such as early-onset pre-eclampsia, malperfusion generates high levels of oxidative stress, causing release of factors that precipitate the maternal syndrome. Further experiments are required using genuine trophoblast progenitor cells and physiological concentrations to fully elucidate the pathways by which oxygen regulates placental development.
Introduction
Oxygen is thought to play a major role in modulating human placental development, which is perhaps not surprising given that this foetal organ evolved principally for the maternal-foetal transfer of respiratory gases. The placenta is unusual in that it has two blood supplies, the maternal utero-placental circulation that supplies oxygen and nutrients and the feto-placental or umbilical circulation that abstracts these to meet the needs of the growing foetus. The balance between supply and demand will determine the oxygen (O2) concentration within the placental tissues, and it is now appreciated that this concentration varies across gestation. In this regard, pregnancy can no longer be considered a continuum but as a process that has two distinct phases, the first trimester lasting until the end of week 12 and the second and third trimesters extending until term. These phases correspond to the embryonic and foetal periods of development, respectively. The transition is associated with a three-fold rise in the intraplacental O2 concentration that must be spatially co-ordinated, for it represents a significant challenge to the placental tissues. Failure of the transition to occur correctly is associated with complications of pregnancy ranging from miscarriage to pre-eclampsia.
Central to any consideration of O2 is the concept of generation of free radicals, molecular species with unpaired electrons. The superoxide anion (O2.−) is constantly formed under aerobic conditions within mitochondria due to the leakage of electrons from the enzymatic complexes of the electron transport chain on to molecular O2, in particular from complex III. The rate of formation is proportional to the prevailing O2 concentration, and under physiological conditions, superoxide acts as an important signalling intermediate, regulating gene expression and cell metabolism to suit the prevailing conditions. If, however, production exceeds the antioxidant defences, then indiscriminate damage can occur to any biomolecule in the immediate vicinity, often initiating chain reactions. This condition is referred to as oxidative stress and may lead to inflammation, senescence, apoptosis and necrosis. Placental oxidative stress lies at the heart of many complications of pregnancy. It is induced primarily through malperfusion of the placenta, but may be exacerbated by deficiencies in the maternal antioxidant defences caused by malnutrition or genetic mutations.
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