Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia

Abstract

Preeclampsia (PE) is a multifactorial pregnancy disease, characterized by new-onset gestational hypertension with (or without) proteinuria or end-organ failure, exclusively observed in humans. It is a leading cause of maternal morbidity affecting 3–7% of pregnant women worldwide. PE pathophysiology could result from abnormal placentation due to a defective trophoblastic invasion and an impaired remodeling of uterine spiral arteries, leading to a poor adaptation of utero-placental circulation. This would be associated with hypoxia/reoxygenation phenomena, oxygen gradient fluctuations, altered antioxidant capacity, oxidative stress, and reduced nitric oxide (NO) bioavailability. This results in part from the reaction of NO with the radical anion superoxide (O 2 •− ), which produces peroxynitrite ONOO - , a powerful pro-oxidant and inflammatory agent. Another mechanism is the progressive inhibition of the placental endothelial nitric oxide synthase (eNOS) by oxidative stress, which results in eNOS uncoupling via several events such as a depletion of the eNOS substrate L-arginine due to increased arginase activity, an oxidation of the eNOS cofactor tetrahydrobiopterin (BH4), or eNOS post-translational modifications (for instance by S -glutathionylation). The uncoupling of eNOS triggers a switch of its activity from a NO-producing enzyme to a NADPH oxidase-like system generating O 2 •− , thereby potentiating ROS production and oxidative stress. Moreover, in PE placentas, eNOS could be post-translationally modified by lipid peroxidation-derived aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to inhibit eNOS activity and NO production. This review summarizes the dysfunction of placental eNOS evoked by oxidative stress and lipid peroxidation products, and the potential consequences on PE pathogenesis.

Newborns of Mothers with Venous Disease during Pregnancy Show Increased Levels of Lipid Peroxidation and Markers of Oxidative Stress and Hypoxia in the Umbilical Cord

“…This abnormal increase in NOX-1 and NOX-2 could critically affect the blood vessels of the cord, which in turn can negatively affect its function. NOX-1 is the main producer of ROS during pregnancy, and its levels are substantially increased under pathological conditions [ 38 , 39 , 40 ]. NOX-2 levels are also elevated due to the development of gestational complications and are closely involved in the deregulation of some key cellular products, such as vascular endothelial growth factor (VEGF), and in the process of angiogenesis [ 41 ].…”

The Association of Familial Hypertension and Risk of Gestational Hypertension and Preeclampsia

“…The etiology of GH/PE is not fully understood yet. Among many factors, genetic, metabolic, immunological and environmental factors are taken into consideration [ 2 , 7 , 29 , 30 , 31 ]. Excessive oxidative stress, inflammation and endothelial disorders are key elements of pathogenesis of GH and PE [ 2 , 7 , 32 ].…”

Modulation by antenatal therapies of cardiovascular and renal programming in male and female offspring of preeclamptic rats

“…Considering the key roles of inflammatory and oxidative pathways in biological offence provoked by endothelin and TXA2 pathways (Possomato-Vieira and Khalil 2016;Guerby et al 2021), the possible involvement of these molecular entities in cardiorenal complications seen in offspring of PE rats were investigated. For this purpose, cardiac and renal levels of TNF-α, a potent inflammatory cytokine with a major role in cellular apoptosis and necrosis (Kalantar et al 2013;Sallam et al 2018), and 8-isoprostane, a reliable marker of lipid peroxidation and oxidative stress (Braekke et al 2006), were measured in adult offspring.…”