Oxidative Stress in Preeclampsia and Placental Diseases

Abstract

Preeclampsia is a persistent hypertensive gestational disease characterized by high blood pressure and proteinuria, which presents from the second trimester of pregnancy. At the cellular level, preeclampsia has largely been associated with the release of free radicals by the placenta. Placenta-borne oxidative and nitrosative stresses are even sometimes considered as the major molecular determinants of the maternal disease. In this review, we present the recent literature evaluating free radical production in both normal and pathological placentas (including preeclampsia and other major pregnancy diseases), in humans and animal models. We then assess the putative effects of these free radicals on the placenta and maternal endothelium. This analysis was conducted with regard to recent papers and possible therapeutic avenues.

Keywords: oxidative stress; placenta; preeclampsia; pregnancy; vascular endothelium.

Figure 1

Oxidative stress plays a central role in the physiopathology of preeclampsia. Schematic of the principal sources of oxidative stress and its antioxidant mechanisms. The mitochondria, endoplasmic reticulum (ER), and nuclear membrane produce anions as a byproduct of the auto-oxidation of electron transport chain (ETC) components. ROS are also produced as a consequence of arachidonic acid metabolism by Cyclooxygenase 2 (COX-2), Lipoxygenases, Xanthine Oxydase (XO), and Cytochrome P450. NADPH oxidases (NOX) are another significant source of ROS. NOX generates superoxide (O₂^•−) by transferring electrons from NADPH inside the cell across its membrane and coupling them to O₂. eNO synthase (eNOS) can generate O₂^•− and H₂O_2, specifically when the concentrations of its substrate, l-arginine, or its cofactor, tetrahydrobiopterin (BH4), are low. When intracellular ROS production increases (especially O₂^•− ions), •NO may react with ROS to form peroxynitrite (ONOO⁻). Superoxide is rapidly dismutated to H₂O₂ by superoxide dismutase (SOD). H₂O₂ can be transformed into H₂O and O₂ by catalase and glutathione peroxidase (GPX). However, in the presence of Fe²⁺, and through Fenton’s reaction, H₂O₂ can generate the highly reactive radical hydroxyl (OH^•).

Figure 2

The placenta is the interface between mother and fetus. The placenta plays an indispensable and multifunctional role as the interface between the two adjoined organisms, regulating immunological dialogue and tolerance, nutrient and gas exchange, and producing hormones essential for pregnancy. The first trimester of gestation in humans is characterized by general hypoxia in the intervillous space, as many maternal spiral arteries are plugged with extravillous trophoblast cells, preventing maternal red blood cells from passing into this space. After 12–14 weeks of normal gestation, these placental extravillous trophoblasts colonize the maternal spiraled arteries as far as the proximal third of the myometrium. This innervation leads to the arteries to relax and lose contractile properties, which increases blood flow and raises oxygen partial pressure, thus reversing the previously hypoxic environment. Therefore, oxidative stress normally occurs in the healthy placenta and may in fact be important for its organogenesis. However, in cases of incomplete placentation, this stress occurs at an excessive level and leads to an elevated release of placental debris and vesicles into the maternal circulation. These extracellular vesicles carry active molecules (proteins of microRNA) generated by stressed placental cells. Once in the blood, they meet maternal endothelial cells and potentially transfer their contents, leading to transcriptome alterations and inflammation. Eventually, the endothelium of maternal organs is affected. In the case of preeclampsia, this most heavily occurs in the kidney, liver, and brain.

Figure 3

Schematic representation of first trimester placentas in IUGR, GDM, and spontaneous pregnancy loss. Oxidative stress (OS) is a key characteristic in various placental pathologies. Although the causes of IUGR can be numerous, placental oxidative stress is recurrently found. In the case of spontaneous pregnancy loss, initial onset of the blood flow in the intervillous chamber happens earlier and is less organized than in normal pregnancies, which leads to an increase in oxidative stress in the placenta. In gestational diabetes, variations in maternal glycaemia participate in placental oxidative stress induction. In all the pathologies mentioned, placental oxidative stress leads to various dysfunctions. Key: glucose (blue dots), oxidative stress (OS), Intra-Uterine Growth Restriction (IUGR), and Gestational Diabetes Mellitus (GDM).

Figure 4

Principal mediators and sources of oxidative stress in the preeclamptic endothelium. Circulating factors in the blood of preeclamptic women can act on endothelial cells (ECs) to induce oxidative stress. These include reactive oxygen species (ROS) produced by neutrophils (oxLDL), agonist autoantibodies against angiotensin receptors (AT1-AA), free fetal hemoglobin (HbF), circulating Xanthine oxidase (XO), and cytokines (i.e., TNF-α). In ECs, several enzymatic systems including the electron transport chain, NADPH oxidases, and cyclooxigenases can produce superoxide (O₂^•−). Under certain circumstances, this can lead to increased Arginase II expression, increased asymmetric dimethyl arginine (ADMA), and the loss of the cofactor tetrahydrobiopterin (BH4), and endothelial nitric oxide synthase (eNOS) synthase can become uncoupled. Instead of •NO, uncoupled eNOS produces (O₂^•−). Nitric oxide can then react with O₂^•− to produce peroxynitrite (ONOO⁻), a powerful oxidant whose nitrate proteins can induce DNA damage. Additionally, ONOO⁻ can inhibit eNOS activity. Superoxide scavenging of •NO impairs endothelium-dependent vasodilation. ROS can also down regulate the calcium-activated potassium channels KCa2.3 and KCa3.1, which are important electrical triggers of vasodilation. Figure adapted from [105].