Evidence-based revised view of the pathophysiology of preeclampsia

Asif Ahmed*, Homira Rezai, Sophie Broadway-Stringer

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Preeclampsia is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta. Millions of women risk death to give birth each year and globally each year, almost 300,000 lose their life in this process and over 500,000 babies die as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial oxidative stress is a central phenomenon responsible for the preeclampsia phenotype of high maternal blood pressure and proteinuria. In 1997, it was proposed that preeclampsia arises due to the loss of VEGF activity, possibly due to elevation in anti-angiogenic factor, soluble Flt-1 (sFlt-1). Researchers showed that high sFlt-1 and soluble endoglin (sEng) elicit the severe preeclampsia phenotype in pregnant rodents. We demonstrated that heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway prevents placental stress and suppresses sFlt-1 and sEng release. Likewise, hydrogen sulphide (H2S)/cystathionine-γ-lyase (Cth) systems limit sFlt-1 and sEng and protect against the preeclampsia phenotype in mice. Importantly, H2S restores placental vasculature, and in doing so improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, preeclampsia is triggered. In this review, we discuss what are the hypotheses and models for the pathophysiology of preeclampsia on the basis of Bradford Hill causation criteria for disease causation and how further in vivo experimentation is needed to establish ‘proof of principle’. Hypotheses that fail to meet the Bradford Hill causation criteria include abnormal spiral artery remodelling and inflammation and should be considered associated or consequential to the disorder. In contrast, the protection against cellular stress hypothesis that states that the protective pathways mitigate cellular stress by limiting elevation of anti-angiogenic factors or oxidative stress and the subsequent clinical signs of preeclampsia appear to fulfil most of Bradford Hill causation criteria. Identifying the candidates on the roadmap to this pathway is essential in developing diagnostics and therapeutics to target the pathogenesis of preeclampsia.

Original languageEnglish
Title of host publicationHypertension: from basic research to clinical practice
EditorsMd. Shahidul Islam
Place of PublicationCham (CH)
PublisherSpringer
Pages355-374
Number of pages20
Volume2
ISBN (Electronic)978-3-319-44251-8
ISBN (Print)978-3-319-44250-1
DOIs
Publication statusPublished - 2017

Publication series

NameAdvances in Experimental Medicine and Biology
PublisherSpringer
Volume956
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019
NameAdvances in Internal Medicine
PublisherSpringer
ISSN (Print)2367-0177
ISSN (Electronic)2367-0185

Fingerprint

Pre-Eclampsia
Oxidative stress
Angiogenesis Inducing Agents
Cystathionine
Hydrogen Sulfide
Heme Oxygenase-1
Lyases
Causality
Blood pressure
Carbon Monoxide
Vascular Endothelial Growth Factor A
Molecules
Phenotype
Oxidative Stress
Mothers
Pregnancy
Fetal Development
Proteinuria
Placenta
Blood Vessels

Keywords

  • activin A
  • angiogenic factors
  • gasotransmitter
  • HO-1
  • hypoxia
  • inflammation
  • microRNA
  • oxidative stress
  • preeclampsia
  • SFlt-1

Cite this

Ahmed, A., Rezai, H., & Broadway-Stringer, S. (2017). Evidence-based revised view of the pathophysiology of preeclampsia. In M. S. Islam (Ed.), Hypertension: from basic research to clinical practice (Vol. 2, pp. 355-374). (Advances in Experimental Medicine and Biology; Vol. 956), (Advances in Internal Medicine). Cham (CH): Springer. https://doi.org/10.1007/5584_2016_168
Ahmed, Asif ; Rezai, Homira ; Broadway-Stringer, Sophie. / Evidence-based revised view of the pathophysiology of preeclampsia. Hypertension: from basic research to clinical practice. editor / Md. Shahidul Islam . Vol. 2 Cham (CH) : Springer, 2017. pp. 355-374 (Advances in Experimental Medicine and Biology). (Advances in Internal Medicine).
@inbook{78a16453ecfa450cb60a9f0537893d14,
title = "Evidence-based revised view of the pathophysiology of preeclampsia",
abstract = "Preeclampsia is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta. Millions of women risk death to give birth each year and globally each year, almost 300,000 lose their life in this process and over 500,000 babies die as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial oxidative stress is a central phenomenon responsible for the preeclampsia phenotype of high maternal blood pressure and proteinuria. In 1997, it was proposed that preeclampsia arises due to the loss of VEGF activity, possibly due to elevation in anti-angiogenic factor, soluble Flt-1 (sFlt-1). Researchers showed that high sFlt-1 and soluble endoglin (sEng) elicit the severe preeclampsia phenotype in pregnant rodents. We demonstrated that heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway prevents placental stress and suppresses sFlt-1 and sEng release. Likewise, hydrogen sulphide (H2S)/cystathionine-γ-lyase (Cth) systems limit sFlt-1 and sEng and protect against the preeclampsia phenotype in mice. Importantly, H2S restores placental vasculature, and in doing so improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, preeclampsia is triggered. In this review, we discuss what are the hypotheses and models for the pathophysiology of preeclampsia on the basis of Bradford Hill causation criteria for disease causation and how further in vivo experimentation is needed to establish ‘proof of principle’. Hypotheses that fail to meet the Bradford Hill causation criteria include abnormal spiral artery remodelling and inflammation and should be considered associated or consequential to the disorder. In contrast, the protection against cellular stress hypothesis that states that the protective pathways mitigate cellular stress by limiting elevation of anti-angiogenic factors or oxidative stress and the subsequent clinical signs of preeclampsia appear to fulfil most of Bradford Hill causation criteria. Identifying the candidates on the roadmap to this pathway is essential in developing diagnostics and therapeutics to target the pathogenesis of preeclampsia.",
keywords = "activin A, angiogenic factors, gasotransmitter, HO-1, hypoxia, inflammation, microRNA, oxidative stress, preeclampsia, SFlt-1",
author = "Asif Ahmed and Homira Rezai and Sophie Broadway-Stringer",
year = "2017",
doi = "10.1007/5584_2016_168",
language = "English",
isbn = "978-3-319-44250-1",
volume = "2",
series = "Advances in Experimental Medicine and Biology",
publisher = "Springer",
pages = "355--374",
editor = "{Islam }, {Md. Shahidul}",
booktitle = "Hypertension: from basic research to clinical practice",
address = "Germany",

}

Ahmed, A, Rezai, H & Broadway-Stringer, S 2017, Evidence-based revised view of the pathophysiology of preeclampsia. in MS Islam (ed.), Hypertension: from basic research to clinical practice. vol. 2, Advances in Experimental Medicine and Biology, vol. 956, Advances in Internal Medicine, Springer, Cham (CH), pp. 355-374. https://doi.org/10.1007/5584_2016_168

Evidence-based revised view of the pathophysiology of preeclampsia. / Ahmed, Asif; Rezai, Homira; Broadway-Stringer, Sophie.

Hypertension: from basic research to clinical practice. ed. / Md. Shahidul Islam . Vol. 2 Cham (CH) : Springer, 2017. p. 355-374 (Advances in Experimental Medicine and Biology; Vol. 956), (Advances in Internal Medicine).

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Evidence-based revised view of the pathophysiology of preeclampsia

AU - Ahmed, Asif

AU - Rezai, Homira

AU - Broadway-Stringer, Sophie

PY - 2017

Y1 - 2017

N2 - Preeclampsia is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta. Millions of women risk death to give birth each year and globally each year, almost 300,000 lose their life in this process and over 500,000 babies die as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial oxidative stress is a central phenomenon responsible for the preeclampsia phenotype of high maternal blood pressure and proteinuria. In 1997, it was proposed that preeclampsia arises due to the loss of VEGF activity, possibly due to elevation in anti-angiogenic factor, soluble Flt-1 (sFlt-1). Researchers showed that high sFlt-1 and soluble endoglin (sEng) elicit the severe preeclampsia phenotype in pregnant rodents. We demonstrated that heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway prevents placental stress and suppresses sFlt-1 and sEng release. Likewise, hydrogen sulphide (H2S)/cystathionine-γ-lyase (Cth) systems limit sFlt-1 and sEng and protect against the preeclampsia phenotype in mice. Importantly, H2S restores placental vasculature, and in doing so improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, preeclampsia is triggered. In this review, we discuss what are the hypotheses and models for the pathophysiology of preeclampsia on the basis of Bradford Hill causation criteria for disease causation and how further in vivo experimentation is needed to establish ‘proof of principle’. Hypotheses that fail to meet the Bradford Hill causation criteria include abnormal spiral artery remodelling and inflammation and should be considered associated or consequential to the disorder. In contrast, the protection against cellular stress hypothesis that states that the protective pathways mitigate cellular stress by limiting elevation of anti-angiogenic factors or oxidative stress and the subsequent clinical signs of preeclampsia appear to fulfil most of Bradford Hill causation criteria. Identifying the candidates on the roadmap to this pathway is essential in developing diagnostics and therapeutics to target the pathogenesis of preeclampsia.

AB - Preeclampsia is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta. Millions of women risk death to give birth each year and globally each year, almost 300,000 lose their life in this process and over 500,000 babies die as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial oxidative stress is a central phenomenon responsible for the preeclampsia phenotype of high maternal blood pressure and proteinuria. In 1997, it was proposed that preeclampsia arises due to the loss of VEGF activity, possibly due to elevation in anti-angiogenic factor, soluble Flt-1 (sFlt-1). Researchers showed that high sFlt-1 and soluble endoglin (sEng) elicit the severe preeclampsia phenotype in pregnant rodents. We demonstrated that heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway prevents placental stress and suppresses sFlt-1 and sEng release. Likewise, hydrogen sulphide (H2S)/cystathionine-γ-lyase (Cth) systems limit sFlt-1 and sEng and protect against the preeclampsia phenotype in mice. Importantly, H2S restores placental vasculature, and in doing so improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, preeclampsia is triggered. In this review, we discuss what are the hypotheses and models for the pathophysiology of preeclampsia on the basis of Bradford Hill causation criteria for disease causation and how further in vivo experimentation is needed to establish ‘proof of principle’. Hypotheses that fail to meet the Bradford Hill causation criteria include abnormal spiral artery remodelling and inflammation and should be considered associated or consequential to the disorder. In contrast, the protection against cellular stress hypothesis that states that the protective pathways mitigate cellular stress by limiting elevation of anti-angiogenic factors or oxidative stress and the subsequent clinical signs of preeclampsia appear to fulfil most of Bradford Hill causation criteria. Identifying the candidates on the roadmap to this pathway is essential in developing diagnostics and therapeutics to target the pathogenesis of preeclampsia.

KW - activin A

KW - angiogenic factors

KW - gasotransmitter

KW - HO-1

KW - hypoxia

KW - inflammation

KW - microRNA

KW - oxidative stress

KW - preeclampsia

KW - SFlt-1

UR - https://link.springer.com/chapter/10.1007%2F5584_2016_168

UR - http://www.scopus.com/inward/record.url?scp=85019189477&partnerID=8YFLogxK

U2 - 10.1007/5584_2016_168

DO - 10.1007/5584_2016_168

M3 - Chapter

AN - SCOPUS:85019189477

SN - 978-3-319-44250-1

VL - 2

T3 - Advances in Experimental Medicine and Biology

SP - 355

EP - 374

BT - Hypertension: from basic research to clinical practice

A2 - Islam , Md. Shahidul

PB - Springer

CY - Cham (CH)

ER -

Ahmed A, Rezai H, Broadway-Stringer S. Evidence-based revised view of the pathophysiology of preeclampsia. In Islam MS, editor, Hypertension: from basic research to clinical practice. Vol. 2. Cham (CH): Springer. 2017. p. 355-374. (Advances in Experimental Medicine and Biology). (Advances in Internal Medicine). https://doi.org/10.1007/5584_2016_168