Oxidative stress and endothelial function in normal pregnancy and preeclampsia
5 July 2018
UAntwerp - Campus Drie Eiken - Building O - Auditorium O5 - Universiteitsplein 1 - 2610 Wilrijk (route: UAntwerpen, Campus Drie Eiken
Prof Y. Jacquemyn & Prof M. Spaanderman
PhD defence Dominique Mannaerts -Faculty of Medicine and Health Sciences
Abstract (Presentation in Dutch)
Background: During normal pregnancy, placental oxidative stress (OS) is present during all three trimesters and is necessary to obtain normal cell function. However, if OS reaches a certain level, pregnancy complications might arise. In preeclampsia (PE), a dangerous pregnancy specific hypertensive disorder, OS induced in the ischemic placenta causes a systemic inflammatory response and activates maternal endothelial cells. In this study, we aimed to quantify superoxide concentrations (as a measure of systemic OS) using electron paramagnetic resonance (EPR) and correlate them to markers of systemic inflammation, iron status and vascular function.
Methods: One hundred women with a healthy pregnancy (HP), 16 non-pregnant controls (NP) and 33 PE patients (32±3.3weeks) were included. During HP, blood samples for superoxide, neutrophil to lymphocyte ratio (NLR), mean platelet volume (MPV) and iron status were taken at 10, 25 and 39 weeks. Vascular measurements for arterial stiffness (carotid-femoral pulse wave velocity (CF-PWV), augmentation index (AIx), augmentation Pressure (AP)) and endothelial function (flow mediated dilatation (FMD), low-flow mediated constriction (L-FMC) and peripheral arterial tonometry (PAT)) were performed at 12 and 35 weeks. In PE, all measurements were performed at diagnosis. CMH (1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine) was used as spin probe for EPR, since the formed CM radical corresponds to the amount of superoxide.
Results: Superoxide concentration remains stable during pregnancy (p=0.92), but is significantly higher compared to the NP controls (p<0.0001). At 25 weeks, there is a significant positive correlation between superoxide and ferritin concentration. (p=0.04) In PE, superoxide, systemic inflammation and iron status are much higher compared to HP (all p<0.001). During HP, superoxide concentrations correlate significantly with arterial stiffness (all p<0.04), while in PE superoxide is significantly correlated to microvascular endothelial function (p=0.03). Overall endothelial dysfunction is present in PE (FMD HP 9.09±4.20 vs PE 5.21±4.47, p=0.0004; L-FMC HP -1.90±2.66 vs PE -0.40±2.09, p=0.03). L-FMC gradually elevates during the course of a HP (1st trim -0.31±1.75 vs 3rd trim -1.97±3.02, p<0.0001) and is present in 85% of women in the third trimester. In NP, only 27% of women has L-FMC. In PE, L-FMC is present in 50% of cases. Arterial stiffness is increased in PE (all p<0.0001).
Conclusions: During HP there is an increased but stable oxidative environment, which is correlated to ferritin concentration. If superoxide levels increase, there is an augmentation in arterial stiffness. In PE pregnancies, systemic inflammation and superoxide concentrations are higher and result in a deterioration of endothelial function. Together, these findings support the hypothesis that PE is characterized by dysfunction of both resting and recruitable endothelial capacity and that the amount of OS directly corresponds to vascular function.