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Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium.
J Exp Med 2019; 216(8):1874-1890JE

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.

Authors+Show Affiliations

Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.Feinberg Cardiovascular and Renal Research Institute, Division of Nephrology/Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL.Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT.Department of Medicine, Veterans Affairs Connecticut Healthcare System, Yale University, New Haven, CT.Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE, Cambridge, MA. Complex Biological Systems Alliance, Medford, MA.Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE, Cambridge, MA. Complex Biological Systems Alliance, Medford, MA.Cancer Genetics Group, WuXi NextCODE, Cambridge, MA.Feinberg Cardiovascular and Renal Research Institute, Division of Nephrology/Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL.Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE, Cambridge, MA tchittenden@wuxinextcode.com. Complex Biological Systems Alliance, Medford, MA. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT michael.simons@yale.edu. Department of Cell Biology, Yale University School of Medicine, New Haven, CT.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31196980

Citation

Ricard, Nicolas, et al. "Endothelial ERK1/2 Signaling Maintains Integrity of the Quiescent Endothelium." The Journal of Experimental Medicine, vol. 216, no. 8, 2019, pp. 1874-1890.
Ricard N, Scott RP, Booth CJ, et al. Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium. J Exp Med. 2019;216(8):1874-1890.
Ricard, N., Scott, R. P., Booth, C. J., Velazquez, H., Cilfone, N. A., Baylon, J. L., ... Simons, M. (2019). Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium. The Journal of Experimental Medicine, 216(8), pp. 1874-1890. doi:10.1084/jem.20182151.
Ricard N, et al. Endothelial ERK1/2 Signaling Maintains Integrity of the Quiescent Endothelium. J Exp Med. 2019 Aug 5;216(8):1874-1890. PubMed PMID: 31196980.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium. AU - Ricard,Nicolas, AU - Scott,Rizaldy P, AU - Booth,Carmen J, AU - Velazquez,Heino, AU - Cilfone,Nicholas A, AU - Baylon,Javier L, AU - Gulcher,Jeffrey R, AU - Quaggin,Susan E, AU - Chittenden,Thomas W, AU - Simons,Michael, Y1 - 2019/06/13/ PY - 2018/11/20/received PY - 2019/03/12/revised PY - 2019/05/08/accepted PY - 2020/02/05/pmc-release PY - 2019/6/15/pubmed PY - 2019/6/15/medline PY - 2019/6/15/entrez SP - 1874 EP - 1890 JF - The Journal of experimental medicine JO - J. Exp. Med. VL - 216 IS - 8 N2 - 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. SN - 1540-9538 UR - https://www.unboundmedicine.com/medline/citation/31196980/Endothelial_ERK1/2_signaling_maintains_integrity_of_the_quiescent_endothelium L2 - http://jem.rupress.org/cgi/pmidlookup?view=long&pmid=31196980 DB - PRIME DP - Unbound Medicine ER -