Hypoxia and sFlt-1 in Preeclampsia: The “Chicken-and-Egg” Question

Preeclampsia is a disorder of pregnancy that is usually characterized by the appearance of proteinuria and hypertension during the third trimester of pregnancy (1). It is a common disorder, occurring in 5% of all pregnancies, and often requires premature delivery of the baby. Occasionally, preeclampsia may lead to seizures and multiorgan dysfunction in the mother with severe morbidity and even mortality. Preeclampsia occurs only in the presence of placenta and remits dramatically postpartum, after the placenta has been delivered (2). The placentae of preeclamptic women appear abnormal, with evidence of underperfusion and ischemia. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles (3, 4). Overwhelming evidence points to endothelial dysfunction as the central mechanism in the pathogenesis of the maternal syndrome in preeclampsia (5). This has led to a hypothesis put forth by Roberts et al. (6, 7) that the ischemic placenta secretes soluble factors into the maternal vasculature. This, in turn, induces endothelial dysfunction and the clinical features of preeclampsia. Several groups including our laboratory have recently presented evidence that excess secretion of a naturally occurring antiangiogenic molecule of placental origin referred to as soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1) may cause the maternal syndrome (8–14). sFlt-1 acts by antagonizing proangiogenic molecules such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) (15). The excess sFlt-1 production in preeclampsia has been hypothesized to be secondary to placental ischemia/hypoxia (12). However, it was unclear how hypoxia would affect the net angiogenic balance in the placenta because VEGF, a proangiogenic molecule, is also up-regulated by hypoxia (16). A report in this issue of Endocrinology [Nagamatsu et al. (17)] provides new evidence that effects of hypoxia are cell type specific and that in placental cytotrophoblasts (in contrast to endothelial cells), hypoxia induces an excess production of sFlt-1. This leads to VEGF deficiency and, consequently, an antiangiogenic state.