Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders

Abstract

Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Keywords: bronchopulmonary dysplasia; cardiovascular disease; fetal death; fetal hydrops; glomerular endotheliosis; hypertension; intrauterine growth restriction; placental-derived growth factor; proteinuria; soluble endoglin; spiral artery remodeling; twin-to-twin transfusion syndrome; vascular endothelial growth factor.

Figure 1

Spiral artery defects in PE 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 that is adequate to sustain the growing fetus. During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype (left panel). In PE, cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, the invasion of the spiral arteries is shallow, and they remain small-caliber, high-resistance vessels leading to placental ischemia (right panel). NK, natural killer; PE, preeclampsia. Rana. Proangiogenic and antiangiogenic factors in preeclampsia. Am J Obstet Gynecol 2022.

Figure 2

Schematic of the isoforms of placental sFLT1 sFLT1 belongs to a family of alternatively spliced proteins made by the placenta that lack the cytoplasmic and transmembrane domain of the full-length FLT1 receptor. Two major isoforms made in human placentas are shown as sFLT1 and sFLT1–14. sFLT1 family of proteins are secreted extracellularly into maternal circulation as they do not possess the anchoring domains that attach to cell membrane. FLT1, fms-like tyrosine kinase 1; PlGF, placental growth factor; sFLT1, soluble fms-like tyrosine kinase 1; sFLT1–14, soluble fms-like tyrosine kinase 1–14; VEGF, vascular endothelial growth factor. Rana. Proangiogenic and antiangiogenic factors in preeclampsia. Am J Obstet Gynecol 2022.

Figure 3

sFLT1 causes endothelial dysfunction by antagonizing VEGF and PlGF signaling VEGF and PlGF are necessary to maintain endothelial health in several tissues including the kidney and perhaps the placenta. During normal pregnancy, vascular homeostasis is maintained by physiological levels of VEGF and PlGF signaling in the vasculature. In PE, excess placental secretion of sFLT1 inhibits VEGF and PlGF signaling in the vasculature. This results in endothelial cell dysfunction, including decreased prostacyclins, nitric oxide production, and release of procoagulant proteins, leading to the clinical manifestations of PE. PE, preeclampsia; PlGF, placental growth factor; sFLT1, soluble fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor; VEGFR1, vascular endothelial growth factor receptor 1. Rana. Proangiogenic and antiangiogenic factors in preeclampsia. Am J Obstet Gynecol 2022.