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.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…MF decreases the production of anti-angiogenic factors, including soluble forms of receptors of angiogenic factors. Among them, there are the placenta-produced soluble vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), which specifically binds to vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF), and the soluble endoglin, a soluble isomer of endoglin, which inhibits the specific binding of TGF-β1 to its receptor [ 313 , 356 , 357 , 358 ]. Moreover, MF and its combination with other drugs (esomeprazole, sulfasalazine) lead to an increase in the expression of VEGF-A and placental growth factor (PlGF), both powerful activators of angiogenesis, and to a decrease in TNFα-induced expression of endothelin-1, a potent vasoconstrictor [ 356 , 357 ].…”

“…Moreover, MF and its combination with other drugs (esomeprazole, sulfasalazine) lead to an increase in the expression of VEGF-A and placental growth factor (PlGF), both powerful activators of angiogenesis, and to a decrease in TNFα-induced expression of endothelin-1, a potent vasoconstrictor [ 356 , 357 ]. In pregnant women, the increased activity of anti-angiogenic factors induces the systemic endothelial dysfunctions and vasospasm and provokes preeclampsia [ 358 ]. MF treatment of mice with a preeclampsia-like model induced by a six-week high-fat diet (HFD) before pregnancy reduces the blood pressure, prevents the proteinuria, normalizes the fetal and maternal weight, and leads to an improvement of the placental labyrinth and fetal vascular development, impaired in the conditions of preeclampsia [ 359 ].…”

Exosomal microRNA‐139‐5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP‐2 pathway via downregulation of protein tyrosine phosphatase

“…5 As delivery is the only effective way for curing the disease, treatment is mainly concentrated on the management of blood pressure and other clinical manifestations. 6 Successful isolation of mesenchymal stem cells (MSC) from the placental decidua basalis tissue of human PE was reported by Yasser S. Basmaeil et al 7 Furthermore, the exosomes emitted by MSC encompass the curative capacity to hinder apoptosis and stimulate angiogenesis in the placenta. 8 Interestingly, around 60% of the circulating microRNAs (miRNA) is linked with exosomes, and the miRNA in exosomes are resilient to RNase management.…”

Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy

“…VEGF, a familiar angiogenic factor in endothelial cells, not only plays an essential role in placental angiogenesis and vascular recasting but also participates in infiltration, proliferation, and differentiation of trophoblast cells ( Brouillet et al, 2012 ). VEGF is indispensable for a healthy pregnancy but declines in the maternal serum and placenta of preeclamptic women ( Jena et al, 2020 ). MET (10 μM) was found to augment the expression of VEGF to exert proangiogenesis effects under hypoxia and hyperglycemia ( Bakhashab et al, 2016 ).…”