Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

Abstract

Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to serious complications and lifelong disabilities—even death—in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.