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.

For the past decades, growing attention has been given to aspirin use during pregnancy. It favors placentation by its proangiogenic, antithrombotic, and antiinflammatory effects. Therefore, low doses of aspirin are prescribed in the prevention of placenta-mediated complications, mainly preeclampsia and fetal growth restriction.However, questions regarding its clinical application are still debated. Aspirin is effective in preventing preeclampsia in a high-risk population. Most guidelines recommend that risk stratification should rely on medical history. Nevertheless, screening performances dramatically improve if biochemical and biophysical markers are included.Concerning the appropriate timing and dose, latest studies suggest aspirin should be started before 16 weeks of pregnancy and at a daily dose of 100 mg or more. Further studies are needed to improve the identification of patients likely to benefit from prophylactic aspirin. Besides, the role of aspirin in the prevention of fetal growth restriction is still questioned. | INTRODUCTIONPreeclampsia (PE) occurs in 3% to 5% of all pregnancies and is responsible for 70 000 maternal deaths worldwide each year. 1 It is a placenta-mediated complication causing a multisystem disorder.PE is defined as hypertension accompanied by one of the following after the 20th week of pregnancy: proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and new onset cerebral or visual symptoms. 2 Over the past decade, substantial advances have been made in understanding the pathophysiology of PE. 3 However, no curative treatment of PE has been found. Hence, to date, delivery of the placenta is the only treatment. Current management of preterm PE consists in balancing the risks of continuing pregnancy and iatrogenic prematurity. Given its major repercussions and the lack of curative treatment, predicting and preventing PE appear to be a major issue of modern obstetrics. 4Fetal growth restriction (FGR) complicates 5% to 10% of pregnancies. 5 It is a leading cause of premature birth and intrapartum hypoxia.Utero-placental insufficiency is the most common cause of FGR. [5][6][7] As with PE, there is no treatment to reverse placental-related fetal restriction. 8Aspirin has been used for its anti-inflammatory properties since time immemorial. For the last 70 years, it has been widely prescribed in the prevention of coronary and cerebrovascular complications.Early descriptions of PE refer to extensive placental thrombotic lesions. 9 Aspirin was therefore prescribed for its antithrombotic properties. The first evidence of aspirin efficacy in preventing PE was published in 1985. 10 Since then, numerous trials have assessed the efficacy of aspirin in preventing placenta-mediated complications. 11Nevertheless, its mechanism of action has not been fully elucidated, and questions regarding its clinical application remain unanswered. | BASIS OF PATHOPHYSIOLOGYPE originates in early stages of placentation. Placentation starts with extravillous trophoblast (EVT...

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Solar ultraviolet A (UV-A) radiation promotes a huge variety of damages on connective tissues and dermal fibroblasts, including cellular senescence, a major contributor of skin photoaging. The mechanisms of skin photoaging evoked by UV-A partly involve the generation of reactive oxygen species and lipid peroxidation. We previously reported that 4-hydroxynonenal (HNE), a lipid peroxidation-derived aldehyde, forms adducts on elastin in the skins of UV-A irradiated hairless mice, possibly contributing to actinic elastosis. In the present study, we investigated whether and how HNE promotes fibroblast senescence in skin photoaging. Dermal fibroblasts of skins from UV-A-exposed hairless mice exhibited an increased number of γH2AX foci characteristic of cell senescence, together with an accumulation of HNE adducts partly colocalizing with the cytoskeletal protein vimentin. Murine fibroblasts exposed to UV-A radiation (two cycles of 15 J/cm2), or HNE (30 µM, 4 h), exhibited senescence patterns characterized by an increased γH2AX foci expression, an accumulation of acetylated proteins, and a decreased expression of the sirtuin SIRT1. HNE adducts were detected on vimentin in cultured fibroblasts irradiated by UV-A or incubated with HNE. The HNE scavenger carnosine prevented both vimentin modification and fibroblast senescence evoked by HNE in vitro and in the skins of UV-A-exposed mice. Altogether, these data emphasize the role of HNE and lipid peroxidation-derived aldehydes in fibroblast senescence, and confirm the protective effect of carnosine in skin photoaging.

Decreased nitric oxide (NO) bioavailability plays a critical role in the pathophysiology of preeclampsia (PE). Recent evidence indicates that S-glutathionylation may occur on the endothelial nitric oxide synthase (eNOS), leading to eNOS uncoupling, characterized by a decreased NO production and an increased generation of superoxide anion (O 2 •– ). We hypothesized that eNOS glutathionylation may occur in PE placentas and participate in eNOS dysfunction. The glutathionylation of eNOS was investigated in thirteen PE-affected patients and in nine normal pregnancies. Immunofluorescence, confocal microscopy and western-blot experiments carried out on eNOS immunoprecipitates, revealed a high level of eNOS glutathionylation in PE placentas, mostly reversed by dithiotreitol (DTT), thus indicative of S-glutathionylation. In order to investigate whether eNOS glutathionylation may alter trophoblast migration, an important event occurring during early placentation, cultured HTR-8/SVneo human trophoblasts (HTR8) were exposed either to low pO 2 (O 2 1%) or to pO 2 changes (O 2 1–20%), in order to generate oxidative stress. Trophoblasts exposed to low pO 2 , did not undergo oxidative stress nor eNOS S-glutathionylation, and were able to generate NO and migrate in a wound closure model. In contrast, trophoblasts submitted to low/high pO 2 changes, exhibited oxidative stress and a (DTT reversible) S-glutathionylation of eNOS, associated with reduced NO production and migration. The autonomous production of NO seemed necessary for the migratory potential of HTR8, as suggested by the inhibitory effect of eNOS silencing by small interfering RNAs, and the eNOS inhibitor L-NAME, in low pO 2 conditions. Finally, the addition of the NO donor, NOC-18 (5 µM), restored in part the migration of HTR8, thereby emphasizing the role of NO in trophoblast homeostasis. In conclusion, the high level of eNOS S-glutathionylation in PE placentas provides new insights in the mechanism of eNOS dysfunction in this disease.

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