The occurrence of seizures (eclampsia, from the Greek “eklampsis,” sudden flashing) has been a long-known and feared complication of pregnancy, often killing both mother and child. Preeclampsia, or the condition preceding full-blown eclampsia, affects up to 5% of pregnant women and is diagnosed by the onset of hypertension and proteinuria in the second trimester (1). Preeclampsia may eventually progress to glomerular malfunction, thrombocytopenia, liver and brain edema, and associated lifethreatening seizures (2)(Figure 1). Preeclampsia has been sometimes termed the “disease of theories,” as several models for its pathogenesis have been proposed. But, as of today, no satisfactory unifying hypothesis has emerged (1). The restricted occurrence of preeclampsia to humans and primates and the lack of a suitable animal model have hampered the understanding of its pathogenesis (3). In this issue of the JCI, SE Maynard et al.(4) report the novel insight that circulating levels of two angiogenic growth factors, VEGF and placental growth factor (PlGF), may play a more important role than previously believed. In particular, the authors propose that, in pregnant women with preeclampsia, the placenta produces elevated levels of the soluble fms-like tyrosine kinase 1 (sFlt1) receptor, which captures free VEGF and PlGF. As a result, the normal vasculature in the kidney, brain, lungs, and other organs is deprived of essential survival and maintenance signals and becomes dysfunctional (Figure 1). As the authors show in their rodent model, this may lead to the development of hypertension and renal disease, reminiscent of preeclampsia in humans. In another study in this issue, V. Eremina et al.(5) provide additional evidence for a critical role of VEGF in renal disease during preeclampsia. These authors demonstrate that mice lacking one VEGF allele in renal podocytes develop the typical renal pathology found in pregnant women with preeclampsia. These studies therefore shed unprecedented light on the pathogenesis of preeclampsia and offer novel therapeutic opportunities for this disease. sFlt1: a likely candidate preeclampsia factor

For the fetus to develop normally, it must receive sufficient oxygen and nutrients (6). These are supplied via the maternal spiral arteries in the uterus. During normal pregnancy, cytotrophoblasts convert from an epithelial to an endothelial phenotype (a process termed pseudo-vasculogenesis) and invade maternal spiral arteries. This vascular remodeling increases the bulk flow and the supply of nutrients and oxygen to the fetus by the end of the first trimester (7, 8)(Figure 1). Vascular factors such as VEGF, angiopoietins, and ephrins have been implicated in this process (7). In preeclampsia, pseudo-vasculogenesis is defective, and the resultant placental ischemia has been proposed to trigger the release of unknown placenta-derived factors. The latter would induce systemic endothelial dysfunction and thereby contribute to the renal, cardiovascular, and neurological defects of preeclampsia (Figure 1). Despite intensive efforts, the precise nature of the placenta-derived