Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

J Exp Med. 2019 Aug 5;216(8):1874-1890. doi: 10.1084/jem.20182151. Epub 2019 Jun 13.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Deep Learning
  • Disease Models, Animal
  • Endothelin-1 / metabolism
  • Endothelium / metabolism*
  • Epithelial-Mesenchymal Transition / genetics
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypertension / metabolism*
  • MAP Kinase Signaling System / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • RNA-Seq
  • Transfection
  • Transforming Growth Factor beta / metabolism


  • Endothelin-1
  • Transforming Growth Factor beta
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3