Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2

Seshini Gurusinghe, Annie G. Cox, Rahana Abd Rahman, Siow T. Chan, Ruth Muljadi, Harmeet Singh, Bryan Leaw, Joanne C. Mockler, Padma Murthi, Rebecca Lim, Euan M. Wallace

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Introduction Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation. Method We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown. Results Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor–α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. Conclusion Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2.

Original languageEnglish
Pages (from-to)74-85
Number of pages12
JournalPlacenta
Volume60
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

Fingerprint

Trophoblasts
Vascular Endothelial Growth Factor Receptor-1
Angiogenesis Inducing Agents
Oxidative Stress
E-Selectin
Vascular Cell Adhesion Molecule-1
Endothelin-1
Intercellular Adhesion Molecule-1
Pre-Eclampsia
Permeability
resveratrol
Human Umbilical Vein Endothelial Cells
In Vitro Techniques
Transcription Factors
Endothelial Cells
Tumor Necrosis Factor-alpha
Antioxidants
Mothers
Gene Expression

Keywords

  • Activin A
  • Fms-like tyrosine kinase 1
  • Heme oxygenase-1
  • Nuclear factor erythroid 2-related factor-2 (Nrf2)
  • Preeclampsia
  • Resveratrol

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynaecology
  • Developmental Biology

Cite this

Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2. / Gurusinghe, Seshini; Cox, Annie G.; Abd Rahman, Rahana; Chan, Siow T.; Muljadi, Ruth; Singh, Harmeet; Leaw, Bryan; Mockler, Joanne C.; Murthi, Padma; Lim, Rebecca; Wallace, Euan M.

In: Placenta, Vol. 60, 01.12.2017, p. 74-85.

Research output: Contribution to journalArticle

Gurusinghe, S, Cox, AG, Abd Rahman, R, Chan, ST, Muljadi, R, Singh, H, Leaw, B, Mockler, JC, Murthi, P, Lim, R & Wallace, EM 2017, 'Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2', Placenta, vol. 60, pp. 74-85. https://doi.org/10.1016/j.placenta.2017.10.008
Gurusinghe, Seshini ; Cox, Annie G. ; Abd Rahman, Rahana ; Chan, Siow T. ; Muljadi, Ruth ; Singh, Harmeet ; Leaw, Bryan ; Mockler, Joanne C. ; Murthi, Padma ; Lim, Rebecca ; Wallace, Euan M. / Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2. In: Placenta. 2017 ; Vol. 60. pp. 74-85.
@article{028d45ba1aca45c09fe7a7c21685cd03,
title = "Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2",
abstract = "Introduction Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation. Method We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown. Results Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor–α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. Conclusion Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2.",
keywords = "Activin A, Fms-like tyrosine kinase 1, Heme oxygenase-1, Nuclear factor erythroid 2-related factor-2 (Nrf2), Preeclampsia, Resveratrol",
author = "Seshini Gurusinghe and Cox, {Annie G.} and {Abd Rahman}, Rahana and Chan, {Siow T.} and Ruth Muljadi and Harmeet Singh and Bryan Leaw and Mockler, {Joanne C.} and Padma Murthi and Rebecca Lim and Wallace, {Euan M.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1016/j.placenta.2017.10.008",
language = "English",
volume = "60",
pages = "74--85",
journal = "Placenta",
issn = "0143-4004",
publisher = "W.B. Saunders Ltd",

}

TY - JOUR

T1 - Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2

AU - Gurusinghe, Seshini

AU - Cox, Annie G.

AU - Abd Rahman, Rahana

AU - Chan, Siow T.

AU - Muljadi, Ruth

AU - Singh, Harmeet

AU - Leaw, Bryan

AU - Mockler, Joanne C.

AU - Murthi, Padma

AU - Lim, Rebecca

AU - Wallace, Euan M.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Introduction Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation. Method We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown. Results Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor–α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. Conclusion Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2.

AB - Introduction Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation. Method We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown. Results Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor–α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. Conclusion Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2.

KW - Activin A

KW - Fms-like tyrosine kinase 1

KW - Heme oxygenase-1

KW - Nuclear factor erythroid 2-related factor-2 (Nrf2)

KW - Preeclampsia

KW - Resveratrol

UR - http://www.scopus.com/inward/record.url?scp=85032931431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032931431&partnerID=8YFLogxK

U2 - 10.1016/j.placenta.2017.10.008

DO - 10.1016/j.placenta.2017.10.008

M3 - Article

VL - 60

SP - 74

EP - 85

JO - Placenta

JF - Placenta

SN - 0143-4004

ER -