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 (O₂^•-), 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 O₂^•-, 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.

Keywords: Endothelial nitric oxide synthase; Lipid peroxidation; Oxidative stress; Preeclampsia; Reactive oxygen species; S-glutathionylation.

Graphical abstract

Fig. 1

Scheme summarizing the mechanisms, risk factors, and outcomes of PE. PE, preclampsia, GH gestational hypertension, SLE systemic lupus erythematosus, NO nitric oxide, PlGF placental growth factor, sFLT-1 Soluble fms-like tyrosine kinase-1, TXA2 Thromboxane-A2, PAPP-A Pregnancy Associated Plasma Protein-A, sEng soluble endoglin.