Oxygen, the Janus gas; its effects on human placental development and function

Abstract

The accumulation of oxygen in the earth's atmosphere enabled metabolic pathways based on high-energy electron transfers that were capable of sustaining complex multicellular organisms to evolve. This advance came at a price, however, for the high reactivity of oxygen posed a major challenge as biological molecules became susceptible to oxidative damage, resulting in potential loss of function. Many extant physiological systems are therefore adapted, and homeostatically regulated, to supply sufficient oxygen to meet energy demands whilst also protecting cells, and mitochondria in particular, from excessive concentrations that could lead to oxidative damage. The invasive form of implantation displayed by the human conceptus presents particular challenges in this respect. During the first trimester, the conceptus develops in a low oxygen environment that favours organogenesis in the embryo, and cell proliferation and angiogenesis in the placenta. Later in pregnancy, higher oxygen concentrations are required to support the rapid growth of the fetus. This transition, which appears unique to the human placenta, must be negotiated safely for a successful pregnancy. Normally, onset of the maternal placental circulation is a progressive periphery-centre phenomenon, and is associated with extensive villous regression to form the chorion laeve. In cases of miscarriage, onset of the circulation is both precocious and disorganized, and excessive placental oxidative stress and villous regression undoubtedly contribute to loss of the pregnancy. Comparison of experimental and in vivo data indicates that fluctuations in placental oxygen concentration are a more powerful stimulus for the generation of oxidative stress than chronic hypoxia alone. Placental oxidative and endoplasmic reticulum stress appear to play key roles in the pathophysiology of complications of pregnancy, such as intrauterine growth restriction and preeclampsia, through their adverse impacts on placental function and growth. Establishing an inviolable maternal blood supply for the second and third trimesters is therefore one of the most crucial aspects of human placentation.

Fig. 1

Diagrammatic representation of the principal pathways for generation and detoxification of ROS. Under physiological conditions ROS regulate the activity of many homeostatic genes through redox-sensitive transcription factors. If excess ROS are produced, either through exposure to elevated oxygen concentrations or through ischaemia–reperfusion, then peroxynitrite and the highly damaging hydroxyl ion can be formed, leading to indiscriminate oxidative damage of biomolecules.

Fig. 3

Diagrammatic representation of the spectrum of changes that can be induced by ROS, ranging from homeostatic responses on the left to cell death on the right.

Fig. 2

Diagram showing how the delivery of oxygen to cells is regulated in (A) the adult body, and (B) the conceptus during the first trimester to avoid excessive oxidative stress. Plugging of the spiral arteries by extravillous trophoblast may serve to maintain low oxygen concentrations within the embryo during the critical phase of organogenesis. Reproduced from (Jauniaux et al. 2006) with permission.

Fig. 4

Diagrammatic representation of how onset of maternal blood flow (arrowed) in the periphery of the placenta may lead to locally elevated levels of oxidative stress, which through suppression of cell proliferation and stimulation of apoptosis leads to villous regression. The deeper trophoblast invasion beneath the conceptus results in more extensive plugging in the central region of the placenta, where villous development continues. D, decidua; M, myometrium. Reproduced from (Jauniaux et al. 2004) with permission.