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Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1(−/−) mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostai...

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Autores principales: Ricard, Nicolas, Scott, Rizaldy P., Booth, Carmen J., Velazquez, Heino, Cilfone, Nicholas A., Baylon, Javier L., Gulcher, Jeffrey R., Quaggin, Susan E., Chittenden, Thomas W., Simons, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683988/
https://www.ncbi.nlm.nih.gov/pubmed/31196980
http://dx.doi.org/10.1084/jem.20182151
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author Ricard, Nicolas
Scott, Rizaldy P.
Booth, Carmen J.
Velazquez, Heino
Cilfone, Nicholas A.
Baylon, Javier L.
Gulcher, Jeffrey R.
Quaggin, Susan E.
Chittenden, Thomas W.
Simons, Michael
author_facet Ricard, Nicolas
Scott, Rizaldy P.
Booth, Carmen J.
Velazquez, Heino
Cilfone, Nicholas A.
Baylon, Javier L.
Gulcher, Jeffrey R.
Quaggin, Susan E.
Chittenden, Thomas W.
Simons, Michael
author_sort Ricard, Nicolas
collection PubMed
description To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1(−/−) mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.
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spelling pubmed-66839882020-02-05 Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium Ricard, Nicolas Scott, Rizaldy P. Booth, Carmen J. Velazquez, Heino Cilfone, Nicholas A. Baylon, Javier L. Gulcher, Jeffrey R. Quaggin, Susan E. Chittenden, Thomas W. Simons, Michael J Exp Med Research Articles To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1(−/−) mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy. Rockefeller University Press 2019-08-05 2019-06-13 /pmc/articles/PMC6683988/ /pubmed/31196980 http://dx.doi.org/10.1084/jem.20182151 Text en © 2019 Ricard et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Ricard, Nicolas
Scott, Rizaldy P.
Booth, Carmen J.
Velazquez, Heino
Cilfone, Nicholas A.
Baylon, Javier L.
Gulcher, Jeffrey R.
Quaggin, Susan E.
Chittenden, Thomas W.
Simons, Michael
Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
title Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
title_full Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
title_fullStr Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
title_full_unstemmed Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
title_short Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
title_sort endothelial erk1/2 signaling maintains integrity of the quiescent endothelium
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683988/
https://www.ncbi.nlm.nih.gov/pubmed/31196980
http://dx.doi.org/10.1084/jem.20182151
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