Aldosterone, vascular endothelial growth factor, and preeclampsia: a mystery solved?

T he renin–angiotensin system (RAS) is one of the key players in volume and sodium homeostasis. Activation of the RAS leads to vasoconstriction, sodium retention, and volume expansion via the action of angiotensin II and the effector hormone of the RAS, aldosterone. The RAS can also respond to changes in plasma volume; activation of the RAS is seen in states of volume contraction and will lead to restoration of plasma volume. Normal pregnancy is characterized by an increase in maternal plasma volume that is considered necessary for optimal perfusion of the placenta to meet the demands of the developing fetus. This volume expansion is mediated, at least in part, by activation of the maternal RAS with increased levels of renin, angiotensin II, and aldosterone in normotensive pregnant women. 1 This view of the RAS in pregnancy is challenged by a number of observations. First, aldosterone levels are higher than expected from the levels of renin or angiotensin II. 2 Additional stimulation of aldosterone secretion by factors other than angiotensin II has therefore been proposed. Second, activity of the RAS is not limited to the maternal kidneys and vasculature. Components of the RAS can be synthesized in the placenta, and local RAS activity can be found both in the maternal deciduas and in fetal tissues, including the spiral arteries. 3 Third, the effects of an activated RAS in pregnancy are different from those in nongravid women. Most strikingly, normotensive pregnant women are refractory to the vasoconstrictor effect of angiotensin II, 4 which may be one of the factors that explain a lower blood pressure than expected from the relatively high levels of angiotensin II. Through these adaptations of the RAS, the pregnant woman can benefit from its positive effects, in particular from volume expansion, regulation of trophoblast invasion, and angiogenesis. At the same time, the negative effects of the RAS, in particular vasoconstriction and hypertension, can be avoided. Preeclampsia is a hypertensive disorder of pregnancy characterized by hypertension, proteinuria, and edema. It affects 2% to 8% of pregnancies and remains a major cause of maternal and fetal morbidity and mortality worldwide. 5 The pathogenesis of preeclampsia is thought to be triggered by excessive maternal immune response to the developing tro-phoblast leading to placental oxidative stress, hypoperfusion, and hypoxia, and the subsequent release of placental factors causing widespread endothelial dysfunction in the maternal circulation. In turn, the resulting placental hypoperfusion is probably …