PATHOPHYSIOLOGY

Despite intense research, the pathogenesis of pre-eclampsia remains poorly understood. Current evidence, however, suggests there is abnormal remodeling of the uterine spiral arteries, and that the resulting placental ischemia triggers release of antiangiogenic substances that increase blood pressure and cause diffuse endothelial dysfunction. In the glomerulus, endothelial dysfunction leads to proteinuria.

One of the factors that may mediate the connection between placental ischemia and preeclampsia is the soluble fms-like tyrosine kinase-1 receptor (sFlt1). Flt-1 is a membrane-bound receptor for VEGF and placental growth factor (PlGF). In response to ischemia, however, the placenta releases increased quantities of the soluble, unbound splice-variant sFlt-1, which scavenges circulating VEGF and PlGF without completing their normal signal cascades. The effective reduction in VEGF levels is associated with endothelial cell dysfunction and hypertension, since this factor normally induces endothelial nitric oxide. The dysfunctional endothelial cells may also contribute to the elevation in blood pressure by producing a smaller amount of vasodilatory prostaglandins.

Endothelial dysfunction is most prominent in the brain, liver, and kidney. In the kidney, the pathognomonic finding is glomerular endotheliosis, which consists of swollen glomerular endothelial cells and occluded, bloodless capillary lumina. It appears that the dysfunctional endothelial cells permit the passage of protein into the urine, since in contrast to many other proteinuric conditions, the podocytes and their foot processes often appear intact. Protein frequently accumulates in the subendothelial space, producing denseappearing deposits.

The importance of sFlt-1 in the pathogenesis of pre-eclampsia is underscored by the fact that administration of this factor to mice produces hypertension, proteinuria, and glomerular endotheliosis. Not all women with elevated sFlt-1 levels, however, develop preeclampsia, and not all women with preeclampsia have elevated sFlt-1 levels. Thus other factors involved in precipitating preeclampsia continue to be investigated.

The renin-angiotensin-aldosterone system, for example, may also play a role in the pathogenesis of preeclampsia. In normal pregnancy, this axis is stimulated to maintain blood pressure. In preeclampsia, however, there is an exaggerated response to angioten sin II. There are several possible explanations for this difference. First, placental ischemia leads to increased expression of bradykinin B2 receptors, which form het-erodimers with the AT1 angiotensin II receptor. These heterodimers are more sensitive to angiotensin II than normal AT1 receptors. In addition, preeclampsia is associated with increased levels of agonistic anti-AT1 antibodies for unknown reasons.

The events leading to abnormal remodeling of the placental vasculature are also unclear. Recent work, however, has focused attention on the enzyme catechol-O-methyltransferase (COMT), which produces 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated in the third trimester. Both COMT and 2-ME have been shown to be deficient in patients with severe preeclampsia. Pregnant mice that lack COMT are deficient in 2-ME and develop placental hypoxia, high sFlt1 levels, and symptoms of pre-eclampsia that improve when 2-ME is replenished.