Endothelin-1 triggers placental oxidative stress pathways: Putative role in preeclampsia

Context: Preeclampsia ( PE) is a disorder that occurs only during pregnancy. The placenta has a controlling role in this condition. Recent literature suggests that the oxidative stress is a component of PE and plays a main role in the link between decreased placental perfusion and the impaired function of maternal endothelium. Objective: Because the human placenta expresses endothelin-1 (ET-1) and its circulating levels are high in pregnancies complicated with PE, the present study investigated the role of ET-1 on placental oxidative stress pathways. Design: Human placental explants, JEG-3, and primary cytotrophoblast cells were cultured with increasing ET-1 concentrations for 6 and 24 h. Setting: The study was conducted at tertiary clinical care centers in Siena and Padova, Italy Interventions: Human placental explants, JEG-3, and primary cytotrophoblast cells were used to test ET-1 effect. Main Outcome Measure(s): The main outcome measure was ET-1 mRNA and its receptor mRNAs, type A and B, detection by RT-PCR. The common markers of oxidative stress [malondialdehyde (MDA), glutathione (GSH), glutathione disulfide ( GSSG), ascorbic acid ( AA)] as well as cell proliferation and vitality were measured after stimulation periods. Results: ET-1 inhibits cell proliferation and vitality and triggers oxidative stress in the human placenta by altering the balance between oxidant ( increased MDA levels) and antioxidant ( decreased GSH, GSSG, and AA) forces in favor of oxidation. Conclusions: Because MDA damages endothelial cells, whereas GSH, GSSG, and AA protect them, we postulate that ET-1 may be one of the key links between primary placental disorders and the systemic endothelial dysfunction of PE.