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Title: | Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2. | Authors: | Rahman R.;Murthi P.;Lim R.;Chan S.T.;Mockler J.C.;Gurusinghe S.;Cox A.G.;Wallace E.M. ;Leaw B.;Singh H.;Muljadi R. | Monash Health Department(s): | Obstetrics and Gynaecology (Monash Women's) | Institution: | (Gurusinghe, Cox, Rahman, Leaw, Mockler, Lim, Wallace) Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia (Murthi) Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia (Gurusinghe, Cox, Rahman, Chan, Muljadi, Singh, Leaw, Lim, Wallace) The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (Wallace) Monash Women's Services, Monash Health, Clayton, Victoria, Australia | Issue Date: | 16-Nov-2017 | Copyright year: | 2017 | Publisher: | W.B. Saunders Ltd | Place of publication: | United Kingdom | Publication information: | Placenta. 60 (pp 74-85), 2017. Date of Publication: December 2017. | Journal: | Placenta | 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-alpha 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.Copyright © 2017 Elsevier Ltd | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1016/j.placenta.2017.10.008 | ORCID: | Wallace, Euan M.; ORCID: http://orcid.org/0000-0002-4506-5233 | Link to associated publication: | Click here for full text options | PubMed URL: | 29208243 [http://www.ncbi.nlm.nih.gov/pubmed/?term=29208243] | ISSN: | 0143-4004 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/38467 | Type: | Article | Subjects: | endothelin 1/ec [Endogenous Compound] intercellular adhesion molecule 1/ec [Endogenous Compound] *resveratrol/pd [Pharmacology] small interfering RNA/ec [Endogenous Compound] *transcription factor Nrf2/ec [Endogenous Compound] tumor necrosis factor/ec [Endogenous Compound] vascular cell adhesion molecule 1/ec [Endogenous Compound] vasculotropin receptor 1/ec [Endogenous Compound] preeclampsia adjuvant therapy antiangiogenic activity antioxidant activity article cell membrane permeability controlled study *endothelial dysfunction endothelium cell female human human tissue in vitro study oxidative stress placenta disorder placenta tissue priority journal protein expression *trophoblast umbilical vein endothelial cell Western blotting 8 isoprostane/ec [Endogenous Compound] activin A/ec [Endogenous Compound] endothelial leukocyte adhesion molecule 1/ec [Endogenous Compound] preeclampsia priority journal protein expression *trophoblast umbilical vein endothelial cell Western blotting cell membrane permeability Article antioxidant activity adjuvant therapy antiangiogenic activity *endothelial dysfunction endothelium cell female human human tissue in vitro study oxidative stress placenta disorder placenta tissue controlled study |
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