Editor's Formulation

In this issue of Seminars in Reproductive Endo­ crinology, we have explored some of the latest concepts into the causes of preeclampsia. Several important components have been addressed as playing important roles in the pathophysiology of this pregnancy disorder. They include endothelial cell dysfunction, hyperlipidemia, insulin resistance, oxidative stress, lipid peroxidation, deficient anti­ oxidant protection, thromboxane/prostacyclin im­ balance, inflammatory cytokines, leukocyte activa­ tion, failure of erosion of the spiral arteries by invasive trophoblast cells, and placental dysfunc­ tion. In the chapters by Dr. Roberts, Dr. Davidge, and Dr. Taylor et al., the evidence for endothelial dys­ function is summarized, such as increased release of cellular fibronectin, increased plasma levels of endothelin-1, increased mitogenic activity in plasma, altered endothelial procoagulant expression, in­ creased adhesion molecules, decreased production of prostacyclin, and Cr release from endothelial cells. In the chapters by Drs. Lorentzen and Henriksen, Dr. Kaaja, Dr. Taylor et al., and Dr. Hubel, data pertaining to hyperlipidemia are presented, such as increased plasma levels of free fatty acids, triglyc­ erides, very-low-density lipoproteins (VLDL), and small dense LDL. Lipid peroxidation is one of the abnormalities of hyperlipidemia. In the chapters by Dr. Hubel, Dr. Davidge, and Dr. Walsh, the evi­ dence for'increased oxidative stress, increased lipid peroxidation, increased peroxynitrite, altered iron kinetics, and deficient antioxidant protection is re­ viewed. In the chapters by Dr. Clark et al. and Dr. Walker, the role of cytokines is reviewed, as well as the evidence for neutrophil activation. In the chap­ ter by Dr. Walsh, placental dysfunction is reviewed and linked to the systemic manifestation of abnor­ malities in the mother. On the basis of the evidence on preeclampsia presented here, the following formulation for the pathophysiology of preeclampsia can be proposed. Preeclampsia occurs because the interaction be­ tween maternal factors and placental factors results in an abnormal positive feed-forward system that progressively worsens until one of the components, the placenta, is removed. Maternal factors such as hyperlipidemia, lipid peroxidation, leukocyte acti­ vation, and increased inflammatory cytokines may be present in the mother owing to preexisting conditions, such as diabetes, obesity, or hyperlipi­ demia, or they may be caused by the placenta. Pla­ cental dysfunction may be caused by the maternal factors or by poor perfusion caused by persistence of the spiral arteries. Placental dysfunction results in increased secretion of oxidized lipids and/or in­ flammatory cytokines, such as TNFα, that worsen the maternal condition either directly or by activa­ tion of leukocytes as they circulate through the in­ tervillous space. Activated leukocytes, such as neu­ trophils, generate inflammatory cytokines and superoxide, and they adhere to endothelial cells to induce oxidative stress. This, along with hyper­ lipidemia and oxidized lipoproteins, causes wide­ spread dysfunction of endothelial cells. As oxidative stress in the maternal and placental compartments worsens, the ability of antioxidants to offset the ox­ idative stress is overwhelmed, and the clinical symptoms of preeclampsia appear.