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2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway
The endogenous estradiol metabolite 2-methoxyestradiol (2-ME) reduces atherosclerotic lesion formation, while the underlying mechanisms remain obscure. In this work, we investigated the vasodilatory effect of 2-ME and the role of nitric oxide (NO) involved. In vivo studies using noninvasive tail-cuf...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351983/ https://www.ncbi.nlm.nih.gov/pubmed/25748432 http://dx.doi.org/10.1371/journal.pone.0118902 |
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author | Chen, Weiyu Cui, Yuhong Zheng, Shuhui Huang, Jinghe Li, Ping Simoncini, Tommaso Zhang, Yongfu Fu, Xiaodong |
author_facet | Chen, Weiyu Cui, Yuhong Zheng, Shuhui Huang, Jinghe Li, Ping Simoncini, Tommaso Zhang, Yongfu Fu, Xiaodong |
author_sort | Chen, Weiyu |
collection | PubMed |
description | The endogenous estradiol metabolite 2-methoxyestradiol (2-ME) reduces atherosclerotic lesion formation, while the underlying mechanisms remain obscure. In this work, we investigated the vasodilatory effect of 2-ME and the role of nitric oxide (NO) involved. In vivo studies using noninvasive tail-cuff methods showed that 2-ME decreased blood pressure in Sprague Dawley rats. Furthermore, in vitro studies showed that cumulative addition of 2-ME to the aorta caused a dose- and endothelium-dependent vasodilation. This effect was unaffected by the pretreatment with the pure estrogen receptor antagonist ICI 182,780, but was largely impaired by endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or by phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (WM). Moreover, 2-ME(10(−7 ∼)10(−5) M)enhanced phosphorylation of Akt and eNOS and promoted NO release from cultured human umbilical endothelial cells (HUVECs). These effects were blocked by PI3K inhibitor WM, or by the transfection with Akt specific siRNA, indicating that endothelial Akt/eNOS/NO cascade plays a crucial role in 2-ME-induced vasodilation. The peroxisome proliferator-activated receptor γ (PPARγ) mRNA and protein expression were detected in HUVECs and the antagonist GW9662 or the transfection with specific PPARγ siRNA inhibited 2-ME-induced eNOS and Akt phosphorylation, leading to the impairment of NO production and vasodilation. In conclusion, 2-ME induces vasodilation by stimulating NO release. These actions may be mediated by PPARγ and the subsequent activation of Akt/eNOS cascade in vascular endothelial cells. |
format | Online Article Text |
id | pubmed-4351983 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43519832015-03-17 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway Chen, Weiyu Cui, Yuhong Zheng, Shuhui Huang, Jinghe Li, Ping Simoncini, Tommaso Zhang, Yongfu Fu, Xiaodong PLoS One Research Article The endogenous estradiol metabolite 2-methoxyestradiol (2-ME) reduces atherosclerotic lesion formation, while the underlying mechanisms remain obscure. In this work, we investigated the vasodilatory effect of 2-ME and the role of nitric oxide (NO) involved. In vivo studies using noninvasive tail-cuff methods showed that 2-ME decreased blood pressure in Sprague Dawley rats. Furthermore, in vitro studies showed that cumulative addition of 2-ME to the aorta caused a dose- and endothelium-dependent vasodilation. This effect was unaffected by the pretreatment with the pure estrogen receptor antagonist ICI 182,780, but was largely impaired by endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or by phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (WM). Moreover, 2-ME(10(−7 ∼)10(−5) M)enhanced phosphorylation of Akt and eNOS and promoted NO release from cultured human umbilical endothelial cells (HUVECs). These effects were blocked by PI3K inhibitor WM, or by the transfection with Akt specific siRNA, indicating that endothelial Akt/eNOS/NO cascade plays a crucial role in 2-ME-induced vasodilation. The peroxisome proliferator-activated receptor γ (PPARγ) mRNA and protein expression were detected in HUVECs and the antagonist GW9662 or the transfection with specific PPARγ siRNA inhibited 2-ME-induced eNOS and Akt phosphorylation, leading to the impairment of NO production and vasodilation. In conclusion, 2-ME induces vasodilation by stimulating NO release. These actions may be mediated by PPARγ and the subsequent activation of Akt/eNOS cascade in vascular endothelial cells. Public Library of Science 2015-03-06 /pmc/articles/PMC4351983/ /pubmed/25748432 http://dx.doi.org/10.1371/journal.pone.0118902 Text en © 2015 Chen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Chen, Weiyu Cui, Yuhong Zheng, Shuhui Huang, Jinghe Li, Ping Simoncini, Tommaso Zhang, Yongfu Fu, Xiaodong 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway |
title | 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway |
title_full | 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway |
title_fullStr | 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway |
title_full_unstemmed | 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway |
title_short | 2-Methoxyestradiol Induces Vasodilation by Stimulating NO Release via PPARγ/PI3K/Akt Pathway |
title_sort | 2-methoxyestradiol induces vasodilation by stimulating no release via pparγ/pi3k/akt pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351983/ https://www.ncbi.nlm.nih.gov/pubmed/25748432 http://dx.doi.org/10.1371/journal.pone.0118902 |
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