Angiogenesis in the placenta: the role of reactive oxygen species signaling

Abstract

Proper placental development and function are central to the health of both the mother and the fetus during pregnancy. A critical component of healthy placental function is the proper development of its vascular network. Poor vascularization of the placenta can lead to fetal growth restriction, preeclampsia, and in some cases fetal death. Therefore, understanding the mechanisms by which uterine stressors influence the development of the placental vasculature and contribute to placental dysfunction is of central importance to ensuring a healthy pregnancy. In this review we discuss how oxidative stress observed in maternal smoking, maternal obesity, and preeclampsia has been associated with aberrant angiogenesis and placental dysfunction resulting in adverse pregnancy outcomes. We also highlight that oxidative stress can influence the expression of a number of transcription factors important in mediating angiogenesis. Therefore, understanding how oxidative stress affects redox-sensitive transcription factors within the placenta may elucidate potential therapeutic targets for correcting abnormal placental angiogenesis and function.

Figure 1

Oxidative stress throughout human pregnancy and its relation to placental angiogenesis. At the beginning of the first trimester of pregnancy, there are low levels of systemic oxidative stress and no blood flow into the placenta because extravillous trophoblasts (EVTs) (depicted as light purple circles) plug the maternal spiral arteries (depicted in red) in the decidua as shown in the first panel. Between 8 and 12 weeks of gestation, the EVT plug dissipates and the EVTs invade maternal spiral arteries to allow blood to enter the placenta (black arrow), as illustrated in the second panel. This coincides with a sharp increase in maternal oxidative stress. Furthermore, the state of oxidative stress increases with gestational age as depicted by the black curve. The first signs of placental angiogenesis occur at 3 weeks of gestation. However from about 12 weeks onwards, blood vessels (red lines) protrude towards the trophoblastic layers of the villi (outlined in green), where blood exchange between maternal and fetal circulation is optimal (shown in panel three). From about 9–23 weeks of gestation, there is an expansion of the fetal capillary bed by branching and nonbranching angiogenesis (dashed red lines in angiogenesis panel). From 23-24 weeks of gestation, the greatest changes in blood vessel development and villous composition are observed (peak angiogenesis panel) [22, 34]. Angiogenesis continues until term with the maturation of blood vessels and development of a more complex vascular network to facilitate exponential fetal growth (last panel). The horizontal black arrows indicate the approximate time each process depicted in the panels occurs. Note: this graph has been constructed by interpretations of multiple studies reporting findings of systemic oxidative stress markers present in women during normal pregnancy [–40] as studies on placental/uterine oxidative stress are limited [32].

Figure 2

Summary of proposed mechanisms linking maternal smoking, maternal obesity, and preeclampsia with pregnancy complications and adverse fetal outcomes. It is well documented that both the placental vasculature and the state of oxidative stress are altered in pregnancies complicated by maternal smoking, maternal obesity, and preeclampsia (see text). These alterations in the placental vascular network are known to contribute to placental dysfunction and adverse pregnancy outcomes as well as abnormal fetal growth, development, and even death. We hypothesize that an increase in oxidative stress contributes to aberrant signaling in placenta, resulting in changes in processes essential for placental vascular development. This could be a potential mechanism leading to the adverse pregnancy outcomes observed in maternal smoking, maternal obesity, and preeclampsia. The solid arrows represent well documented findings, while the dashed arrow identifies the knowledge gap where more research needs to be done, to clarify the role of oxidative stress in placental angiogenesis.

Figure 3

Placental oxidative stress triggers the expression of transcription factors to regulate angiogenesis and trophoblast invasion. Mitochondria within the placenta (depicted in pale pink) are a major producer of ROS, such as O₂ ^−• which can cause a state of oxidative stress (illustrated in yellow). Oxidative stress within the placenta can act as a signaling pathway to influence the expression of transcription factors, such as KLF8, Ets-1, NFκB, Sp1, Sp3, STAT-3, and Nrf2 (depicted by the grey arrows). These transcription factors regulate the expression and activity of proteins related to angiogenesis and trophoblast invasion (as shown by the lines linking to the invasion and angiogenesis panels).