Molecular Mechanisms of Preeclampsia

Abstract

Preeclampsia is a pregnancy-specific disease characterized by new onset hypertension and proteinuria after 20 wk of gestation. It is a leading cause of maternal and fetal morbidity and mortality worldwide. Exciting discoveries in the last decade have contributed to a better understanding of the molecular basis of this disease. Epidemiological, experimental, and therapeutic studies from several laboratories have provided compelling evidence that an antiangiogenic state owing to alterations in circulating angiogenic factors leads to preeclampsia. In this review, we highlight the role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia.

Figure 1.

VEGF signaling and role of sFlt-1 in maternal endothelial dysfunction. There is mounting evidence that VEGF, and possibly PlGF, are required to maintain endothelial health in several tissues including the kidney and perhaps the placenta. In normal pregnancy, the placenta produces modest concentrations of VEGF, PlGF, and sFlt-1. In preeclampsia, excess placental sFlt-1 binds circulating VEGF and PlGF and prevents their interaction with endothelial cell-surface receptors leading to endothelial dysfunction. (From Karumanchi et al. 2005; reproduced, with permission, from the author.)

Figure 2.

Spiral artery defects in preeclampsia. Exchange of oxygen, nutrients, and waste products between the fetus and the mother depends on adequate placental perfusion by maternal vessels. In normal placental development, invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries, transforming them from small-caliber resistance vessels to high-caliber capacitance vessels capable of providing placental perfusion adequate to sustain the growing fetus. During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as “pseudovasculogenesis” (upper panel). In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, invasion of the spiral arteries is shallow and they remain small caliber, resistance vessels leading to placental ischemia (lower panel). (From Lam et al. 2005; reproduced, with permission, from the author.)

Figure 3.

Schematic of syncytiotrophoblast pathology in preeclampsia. Syncytialization, knot formation, and subsequent microparticle shedding appear to be normal events of pregnancy. Preeclampsia rises from an augmentation of this sequence. Syncytial fragments shed into the maternal circulation are a significant source of circulating sFlt-1 in preeclampsia. (Created from data in Huppertz and Herrler 2005.)

Figure 4.

Summary of the pathogenesis of preeclampsia.