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

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

Research output: Contribution to journalArticleResearchpeer-review

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

Keywords

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

Cite this

Gurusinghe, Seshini ; Cox, Annie G. ; Rahman, Rahana ; Chan, Siow T. ; Muljadi, Ruth ; Singh, Harmeet ; Leaw, Bryan ; Mockler, Joanne C. ; Marshall, Sarah Arwen Emma Madelaine ; 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.
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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 Rahana Rahman and Chan, {Siow T.} and Ruth Muljadi and Harmeet Singh and Bryan Leaw and Mockler, {Joanne C.} and Marshall, {Sarah Arwen Emma Madelaine} and Padma Murthi and Rebecca Lim and Wallace, {Euan M.}",
year = "2017",
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Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2. / Gurusinghe, Seshini; Cox, Annie G.; Rahman, Rahana; Chan, Siow T.; Muljadi, Ruth; Singh, Harmeet; Leaw, Bryan; Mockler, Joanne C.; Marshall, Sarah Arwen Emma Madelaine; Murthi, Padma; Lim, Rebecca; Wallace, Euan M.

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

Research output: Contribution to journalArticleResearchpeer-review

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 - Rahman, Rahana

AU - Chan, Siow T.

AU - Muljadi, Ruth

AU - Singh, Harmeet

AU - Leaw, Bryan

AU - Mockler, Joanne C.

AU - Marshall, Sarah Arwen Emma Madelaine

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

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 -