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Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression.

Publication ,  Journal Article
Boerckel, JD; Chandrasekharan, UM; Waitkus, MS; Tillmaand, EG; Bartlett, R; Dicorleto, PE
Published in: Arterioscler Thromb Vasc Biol
May 2014

OBJECTIVE: Angiogenesis is the formation of new blood vessels through endothelial cell sprouting. This process requires the mitogen-activated protein kinases, signaling molecules that are negatively regulated by the mitogen-activated protein kinase phosphatase-1 (MKP-1). The purpose of this study was to evaluate the role of MKP-1 in neovascularization in vivo and identify associated mechanisms in endothelial cells. APPROACH AND RESULTS: We used murine hindlimb ischemia as a model system to evaluate the role of MKP-1 in angiogenic growth, remodeling, and arteriogenesis in vivo. Genomic deletion of MKP-1 blunted angiogenesis in the distal hindlimb and microvascular arteriogenesis in the proximal hindlimb. In vitro, endothelial MKP-1 depletion/deletion abrogated vascular endothelial growth factor-induced migration and tube formation, and reduced proliferation. These observations establish MKP-1 as a positive mediator of angiogenesis and contrast with the canonical function of MKP-1 as a mitogen-activated protein kinase phosphatase, implying an alternative mechanism for MKP-1-mediated angiogenesis. Cloning and sequencing of MKP-1-bound chromatin identified localization of MKP-1 to exonic DNA of the angiogenic chemokine fractalkine, and MKP-1 depletion reduced histone H3 serine 10 dephosphorylation on this DNA locus and blocked fractalkine expression. In vivo, MKP-1 deletion abrogated ischemia-induced fractalkine expression and macrophage and T-lymphocyte infiltration in distal hindlimbs, whereas fractalkine delivery to ischemic hindlimbs rescued the effect of MKP-1 deletion on neovascular hindlimb recovery. CONCLUSIONS: MKP-1 promoted angiogenic and arteriogenic neovascular growth, potentially through dephosphorylation of histone H3 serine 10 on coding-region DNA to control transcription of angiogenic genes, such as fractalkine. These observations reveal a novel function for MKP-1 and identify MKP-1 as a potential therapeutic target.

Duke Scholars

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

May 2014

Volume

34

Issue

5

Start / End Page

1020 / 1031

Location

United States

Related Subject Headings

  • Transfection
  • Time Factors
  • Signal Transduction
  • Serine
  • RNA Interference
  • Phosphorylation
  • Neovascularization, Physiologic
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice, Inbred C57BL
 

Citation

APA
Chicago
ICMJE
MLA
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Boerckel, J. D., Chandrasekharan, U. M., Waitkus, M. S., Tillmaand, E. G., Bartlett, R., & Dicorleto, P. E. (2014). Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression. Arterioscler Thromb Vasc Biol, 34(5), 1020–1031. https://doi.org/10.1161/ATVBAHA.114.303403
Boerckel, Joel D., Unnikrishnan M. Chandrasekharan, Matthew S. Waitkus, Emily G. Tillmaand, Rebecca Bartlett, and Paul E. Dicorleto. “Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression.Arterioscler Thromb Vasc Biol 34, no. 5 (May 2014): 1020–31. https://doi.org/10.1161/ATVBAHA.114.303403.
Boerckel JD, Chandrasekharan UM, Waitkus MS, Tillmaand EG, Bartlett R, Dicorleto PE. Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression. Arterioscler Thromb Vasc Biol. 2014 May;34(5):1020–31.
Boerckel, Joel D., et al. “Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression.Arterioscler Thromb Vasc Biol, vol. 34, no. 5, May 2014, pp. 1020–31. Pubmed, doi:10.1161/ATVBAHA.114.303403.
Boerckel JD, Chandrasekharan UM, Waitkus MS, Tillmaand EG, Bartlett R, Dicorleto PE. Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression. Arterioscler Thromb Vasc Biol. 2014 May;34(5):1020–1031.

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

May 2014

Volume

34

Issue

5

Start / End Page

1020 / 1031

Location

United States

Related Subject Headings

  • Transfection
  • Time Factors
  • Signal Transduction
  • Serine
  • RNA Interference
  • Phosphorylation
  • Neovascularization, Physiologic
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice, Inbred C57BL