The Role of Oxidative Stress-Induced Senescence in the Pathogenesis of Preeclampsia

Abstract

Preeclampsia is a hypertension condition of human pregnancy that poses a significant risk to pregnant women and their fetus. It complicates about 2-8% of human pregnancies worldwide and displays multifactorial pathogenesis, including increased placental oxidative stress because of disturbed utero-placental blood flow. Recent evidence suggests that increased oxidative stress promotes acceleration of the placental senescence which is implicated in the pathogenesis of preeclampsia. This review focuses on the mechanisms that lead to oxidative stress in preeclamptic patients and examines the role of oxidative stress-induced placental senescence in the pathogenesis of the disease.

Keywords: cellular senescence; ischemia and reperfusion; oxidative stress; placenta; preeclampsia.

Figure 1

Complications associated with preeclampsia. Preeclampsia is an important cause of pregnancy complication that affects about 2–8% of human pregnancies worldwide and poses a significant risk to pregnant women and their fetus. It is characterized by maternal new onset hypertension observed after 20 weeks of gestation with (or without) proteinuria, other maternal organ dysfunction, and/or fetal growth restriction.

Figure 2

Diagram of decidual spiral artery remodeling in healthy pregnancy and in preeclampsia. Prior to remodeling, spiral arteries have an intact endothelium with extracellular matrix and a layer of vascular smooth muscle cells. In healthy pregnancy, extravillous trophoblasts (EVT) migrate and invade into decidual spiral arteries, transforming them into high-flow, low-resistance vessels and increasing the delivery of blood to the intervillous space. EVT invasion replaces the endothelium and destroys most of the musculo-elastic layer, which is replaced by fibrinoid material. In preeclampsia, EVT display less invasive features and fail to sufficiently transform the spiral arteries. The incomplete transformation involves the persistence of smooth muscle cells and lack of trophoblast invasion and fibrinoid deposition. Consequently, there is an intermittent perfusion of the intervillous space leading to repeated waves of hypoxia and reoxygenation.

Figure 3

The dual role of reactive species in aerobes. The formation of several types of reactive species, including reactive oxygen species (ROS) (e.g., superoxide (O₂^•−), hydrogen peroxide (H₂O₂), hydroxyl radical (HO^•), alkoxyl radical (RO^•)) reactive nitrogen species (RNS) (e.g., nitric oxide (^•NO), peroxynitrite (ONOO⁻)), reactive sulfur species (RSS) (e.g., hydrogen sulfide (H₂S)), reactive electrophilic species (RES) (e.g., 4-hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA), 4-oxo-2-nonenal (ONE)), is inevitable in aerobic cells. To prevent oxidative damage, several defense systems coordinate to attenuate them, contributing to the maintenance of a delicate redox balance. Reactive species play a dual role in aerobes: they are beneficial when confined to physiological levels (oxidative eustress), or damaging when their levels exceed a certain level (oxidative distress). They can also activate repair mechanisms or induce adaptive responses.

Figure 4

Sources of reactive oxygen species generation in post-ischemic tissues. Several different sources of reactive species generation have been proposed to contribute to reactive oxygen species generation when oxygen-starved tissues or organs are re-oxygenated. The most likely contributors are mitochondria, xanthine oxidase, NADPH oxidases, and uncoupled nitric oxide synthase. The generated O₂^•− can be converted to downstream ROS, such as H₂O₂, which in turn produces HO^• via a reaction catalyzed by Fe²⁺ (Fenton reaction). HO^• is the most reactive oxidant produced in vivo and triggers unspecific oxidations to all biological molecules.