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

Erlandsson, Lena LU ; Masoumi, Zahra LU orcid ; Hansson, Lucas R. and Hansson, Stefan R. LU orcid (2021) In Journal of Internal Medicine 290(5). p.952-968
Abstract

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... (More)

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.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
extracellular vesicles, ferroptosis, iron, non-erythroid globin, placenta
in
Journal of Internal Medicine
volume
290
issue
5
pages
952 - 968
publisher
Wiley-Blackwell
external identifiers
  • pmid:34146434
  • scopus:85109085584
ISSN
0954-6820
DOI
10.1111/joim.13349
language
English
LU publication?
yes
id
5596d051-fafb-4eec-a398-53213fd7a7c1
date added to LUP
2021-08-13 08:22:11
date last changed
2024-06-16 16:47:48
@article{5596d051-fafb-4eec-a398-53213fd7a7c1,
  abstract     = {{<p>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.</p>}},
  author       = {{Erlandsson, Lena and Masoumi, Zahra and Hansson, Lucas R. and Hansson, Stefan R.}},
  issn         = {{0954-6820}},
  keywords     = {{extracellular vesicles; ferroptosis; iron; non-erythroid globin; placenta}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{952--968}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Internal Medicine}},
  title        = {{The roles of free iron, heme, haemoglobin, and the scavenger proteins haemopexin and alpha-1-microglobulin in preeclampsia and fetal growth restriction}},
  url          = {{http://dx.doi.org/10.1111/joim.13349}},
  doi          = {{10.1111/joim.13349}},
  volume       = {{290}},
  year         = {{2021}},
}