Invasive Cytotrophoblasts Manifest Evidence of Oxidative Stress in Preeclampsia

Abstract

In preeclampsia, poor placental perfusion may result in maternal endothelial dysfunction, but the pathways involved are largely unknown. Candidate placental mediators include products of oxidative stress released into the maternal circulation. Xanthine oxidase has been implicated in postischemic-reperfusion injury via the generation of superoxide anion radicals (superoxide; O 2 .؊ ) and hydrogen peroxide. We examined placentas and placental bed curettings and/or biopsies from preeclamptic control pregnant women to test the hypothesis that xanthine oxidase is a mediator of oxidative stress in placentas from women with preeclampsia. The expression of xanthine dehydrogenase/xanthine oxidase holoenzyme and the activity of xanthine oxidase, the isoform known to generate reactive oxygen species, were increased in a subpopulation of cytotrophoblasts of preeclamptic women. Additionally, the expression of superoxide dismutase, which would scavenge superoxide produced by xanthine oxidase, was reduced in the same cells. Preeclampsia, a pregnancy-specific disorder, is the leading cause of maternal mortality in the Western world and increases perinatal mortality fivefold. The clinical diagnosis is based on the new onset of hypertension and the appearance of proteinuria and edema during pregnancy. It is evident, however, that these findings are a small component of a multisystemic disease that reduces perfusion to virtually all of the organs in the body. 1 The hypothesis has been advanced that much of the disease could be explained by alterations in the function of vascular endothelium. Increasing data support this hypothesis. 2 The more complete hypothesis posits that the placenta, likely in response to reduced perfusion, produces a circulating factor(s) that alters endothelial cell function. 2 Among the candidate molecules are products resulting from oxidative stress. 3 Oxidative stress, the result of freeradical generation in excess of protective mechanisms, is suggested as an important component of other disorders that affect endothelial function, including diabetes and atherosclerosis. 4,5 Evidence for oxidative stress in preeclampsia includes elevated lipid hydroperoxides or their metabolites and reduced plasma antioxidant activity. 3,6 -8 Xanthine oxidase, which metabolizes xanthine and hypoxanthine to uric acid with production of superoxide and hydrogen peroxide, is an integral mediator of reactive oxygen species generation in many settings. Usually, this enzyme is present as the holoenzyme xanthine dehydrogenase/xanthine oxidase (XDH/XO). The dehydrogenase isoform (XDH) converts purines to uric acid with reducton of nicotinamide-adenine dinucleotide (NAD) to reduced NAD (NADH). With hypoxia and in response to several cytokines, XDH/XO synthesis increases, and the conversion of the enzyme to the XO form is enhanced. 9 Reduced organ perfusion and subsequent reperfusion are proposed to result in increased XO during reduced flow and in subsequent formation of reactive oxygen species with reperfusion. The inadequate pla...

AT 1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase

“…Increased nitrotyrosine immunoreactivity has been identified in placentas from preeclamptic women 23 as well as increased xanthine oxidase activity 8 and decreased superoxide dismutase function. Furthermore, evidence for oxidative stress in preeclampsia has accrued from studies of ascorbate radical.…”

“…The identity of the ROS-producing enzyme is imperfectly defined. Many et al 8 recently implicated increased xanthine oxidase expression. NADPH oxidase is a major source for ROS in arteriosclerosis and reperfusion injury.…”

Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy

“…Increased xanthine oxidase in invading trophoblast cells 70 Increased nitrotyrosine resides in fetal blood vessel 71 …”

Nouveaux regards sur la prééclampsie

“…Dans le placenta, le fer stocké dans les syncytiotrophoblastes catalyse (par la réaction de Fenton) la conversion du H 2 O 2 en OH • , un radical extrêmement réactif et cytotoxique, et plusieurs études ont montré que les trophoblastes isolés à partir de placentas prééclamptiques présentent une augmentation de l'activité de la XO par rapport aux trophoblastes isolés de placentas non-pathologiques [26]. Les cellules endothéliales HUVEC (human umbilical vein endothelial cells) traitées par du sérum provenant de femmes prééclamptiques, surexpriment la sous-unité NADPH oxydase gp91 (phox).…”