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.
Highlights
Hypertensive disorders are common pregnancy complications leading to serious outcomes for both mother and fetus
These processes are interconnected with a common downstream impairment of spiral artery remodeling and the excess release of soluble fms-like tyrosine kinase-1, the soluble form of the vascular endothelial growth factor (VEGF) receptor VEGF receptor 1 (VEGFR-1) into maternal circulation [16,17] (Figure 2)
The level of soluble fms-like tyrosine kinase-1 (sFlt-1) in serum is found to be 20–50 times higher in healthy pregnancies as compared to the non-pregnant state, with peak concentrations at term, suggesting its importance in normal pregnancy [36]. It acts as a regulator of placental invasion in healthy pregnancies, maintaining the placental position at an appropriate depth in the uterine wall [37], one study showed trophoblast-derived full-length VEGFR-1 (Flt-1)/sFlt-1 is dispensable in the establishment of pregnancy in mouse placenta [38]
Summary
Hypertensive disorders are common pregnancy complications leading to serious outcomes for both mother and fetus. Recent large-scale microarray studies and the unsupervised clustering of PE patient samples revealed three distinct molecular subclasses of PE: (a) canonical, exhibiting established PE markers and molecular phenotypes; (b) immune response-related; and (c) the subclass representing poor maternal responses to pregnancy These studies show PE to be a multifactorial disease with different molecular pathways marking each group [12,13]. The etiology of PE is still not clear, conditions like defective decidualization, impaired cytotrophoblast invasion, endothelial dysfunction, and inappropriate immune responses to the allogenic fetus are thought to contribute to the disease These processes are interconnected with a common downstream impairment of spiral artery remodeling and the excess release of soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble form of the vascular endothelial growth factor (VEGF) receptor VEGF receptor 1 (VEGFR-1) into maternal circulation [16,17] (Figure 2). This review article discusses the molecular mechanisms involved in the pathogenesis of PE, the delicate balance between VEGF and sFlt-1 in the disease process, and candidate therapeutic approaches
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