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Abl family kinases regulate endothelial barrier function in vitro and in mice.

Publication ,  Journal Article
Chislock, EM; Pendergast, AM
Published in: PLoS One
2013

The maintenance of endothelial barrier function is essential for normal physiology, and increased vascular permeability is a feature of a wide variety of pathological conditions, leading to complications including edema and tissue damage. Use of the pharmacological inhibitor imatinib, which targets the Abl family of non-receptor tyrosine kinases (Abl and Arg), as well as other tyrosine kinases including the platelet-derived growth factor receptor (PDGFR), Kit, colony stimulating factor 1 receptor (CSF1R), and discoidin domain receptors, has shown protective effects in animal models of inflammation, sepsis, and other pathologies characterized by enhanced vascular permeability. However, the imatinib targets involved in modulation of vascular permeability have not been well-characterized, as imatinib inhibits multiple tyrosine kinases not only in endothelial cells and pericytes but also immune cells important for disorders associated with pathological inflammation and abnormal vascular permeability. In this work we employ endothelial Abl knockout mice to show for the first time a direct role for Abl in the regulation of vascular permeability in vivo. Using both Abl/Arg-specific pharmacological inhibition and endothelial Abl knockout mice, we demonstrate a requirement for Abl kinase activity in the induction of endothelial permeability by vascular endothelial growth factor both in vitro and in vivo. Notably, Abl kinase inhibition also impaired endothelial permeability in response to the inflammatory mediators thrombin and histamine. Mechanistically, we show that loss of Abl kinase activity was accompanied by activation of the barrier-stabilizing GTPases Rac1 and Rap1, as well as inhibition of agonist-induced Ca(2+) mobilization and generation of acto-myosin contractility. In all, these findings suggest that pharmacological targeting of the Abl kinases may be capable of inhibiting endothelial permeability induced by a broad range of agonists and that use of Abl kinase inhibitors may have potential for the treatment of disorders involving pathological vascular leakage.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

12

Start / End Page

e85231

Location

United States

Related Subject Headings

  • rap GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • Vascular Endothelial Growth Factor A
  • Thrombin
  • Pyrimidines
  • Proto-Oncogene Proteins c-abl
  • Protein Kinase Inhibitors
  • Piperazines
  • Neuropeptides
  • Mice, Knockout
 

Citation

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Chislock, E. M., & Pendergast, A. M. (2013). Abl family kinases regulate endothelial barrier function in vitro and in mice. PLoS One, 8(12), e85231. https://doi.org/10.1371/journal.pone.0085231
Chislock, Elizabeth M., and Ann Marie Pendergast. “Abl family kinases regulate endothelial barrier function in vitro and in mice.PLoS One 8, no. 12 (2013): e85231. https://doi.org/10.1371/journal.pone.0085231.
Chislock EM, Pendergast AM. Abl family kinases regulate endothelial barrier function in vitro and in mice. PLoS One. 2013;8(12):e85231.
Chislock, Elizabeth M., and Ann Marie Pendergast. “Abl family kinases regulate endothelial barrier function in vitro and in mice.PLoS One, vol. 8, no. 12, 2013, p. e85231. Pubmed, doi:10.1371/journal.pone.0085231.
Chislock EM, Pendergast AM. Abl family kinases regulate endothelial barrier function in vitro and in mice. PLoS One. 2013;8(12):e85231.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

12

Start / End Page

e85231

Location

United States

Related Subject Headings

  • rap GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • Vascular Endothelial Growth Factor A
  • Thrombin
  • Pyrimidines
  • Proto-Oncogene Proteins c-abl
  • Protein Kinase Inhibitors
  • Piperazines
  • Neuropeptides
  • Mice, Knockout