The roles of free iron, heme, haemoglobin, and the scavenger proteins haemopexin and alpha-1-microglobulin in preeclampsia and fetal growth restriction.

BACKGROUND: Preeclampsia (PE) is a complex pregnancy syndrome characterised by maternal hypertension and organ damage after 20 weeks of gestation and is associated with an increased risk of cardiovascular disease later in life. Extracellular haemoglobin (Hb) and its metabolites heme and iron are highly toxic molecules and several defence mechanisms have evolved to protect the tissue. OBJECTIVES: We will discuss the roles of free iron, heme, Hb, and the scavenger proteins haemopexin and alpha-1-microglobulin in pregnancies complicated by PE and fetal growth restriction (FGR). CONCLUSION: In PE, oxidative stress causes syncytiotrophoblast (STB) stress and increased shedding of placental STB-derived extracellular vesicles (STBEV). The level in maternal circulation correlates with the severity of hypertension and supports the involvement of STBEVs in causing maternal symptoms in PE. In PE and FGR, iron homeostasis is changed, and iron levels significantly correlate with the severity of the disease. The normal increase in plasma volume taking place during pregnancy is less for PE and FGR and therefore have a different impact on, for example, iron concentration, compared to normal pregnancy. Excess iron promotes ferroptosis is suggested to play a role in trophoblast stress and lipotoxicity. Non-erythroid α-globin regulates vasodilation through the endothelial nitric oxide synthase pathway, and hypoxia-induced α-globin expression in STBs in PE placentas is suggested to contribute to hypertension in PE. Underlying placental pathology in PE with and without FGR might be amplified by iron and heme overload causing oxidative stress and ferroptosis. As the placenta becomes stressed, the release of STBEVs increases and affects the maternal vasculature.

Assessing erythroferrone and iron homeostasis in preeclamptic and normotensive pregnancies: A retrospective study.

INTRODUCTION: Preeclampsia (PE) is a pregnancy-related disorder associated with maternal hypertension and placental dysfunction. A significant micronutrient during pregnancy is iron, which is important in cellular functions. While iron absorption increases in pregnancy, little is known about the exact mechanisms regulating maternal iron levels and transfer through the placenta in normal and complicated pregnancies. METHODS: In this retrospective study, we investigated the regulation of maternal and placental iron availability and storage, in normotensive and pregnancies complicated by early- or late-onset PE. Methods used were analysis of clinical records, ELISA analysis on plasma samples, immunofluorescent and Prussian Blue analysis on placenta biopsies. RESULTS: Focusing on erythroferrone (ERFE) as a new marker and hormonal regulator of iron, our results demonstrated altered maternal ERFE levels in PE. We are the first to report the expression of ERFE in trophoblasts and indicate its lower levels in early-onset PE placentas. These changes were associated with lower placental transferrin receptor 1 (TfR1) in syncytiotrophoblasts in both early- and late-onset PE. In addition, maternal plasma ERFE levels were elevated in both early- and late-onset PE and hepcidin levels reduced in early-onset PE. Unaltered maternal plasma IL-6 levels suggest mechanism other than inflammation being involved in altered iron regulation in PE pregnancy. DISCUSSION: Our data supports a deregulation in maternal iron bioavailability in early- and late-onset PE vs normotensive pregnancies. The exact role of placental ERFE in regulating maternal-placental-fetal iron transport axis requires further investigation.