Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

Nicolas Ricard, Rizaldy P. Scott, Carmen J. Booth, Heino Velazquez, Nicholas A. Cilfone, Javier L. Baylon, Jeffrey R. Gulcher, Susan E. Quaggin, Thomas W. Chittenden*, Michael Simons

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1874-1890
Number of pages17
JournalJournal of Experimental Medicine
Volume216
Issue number8
DOIs
StatePublished - Aug 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ricard, N., Scott, R. P., Booth, C. J., Velazquez, H., Cilfone, N. A., Baylon, J. L., Gulcher, J. R., Quaggin, S. E., Chittenden, T. W., & Simons, M. (2019). Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium. Journal of Experimental Medicine, 216(8), 1874-1890. https://doi.org/10.1084/jem.20182151