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

Published

Journal Article

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.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.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.

Full Text

Duke Authors

Cited Authors

  • Boerckel, JD; Chandrasekharan, UM; Waitkus, MS; Tillmaand, EG; Bartlett, R; Dicorleto, PE

Published Date

  • May 2014

Published In

Volume / Issue

  • 34 / 5

Start / End Page

  • 1020 - 1031

PubMed ID

  • 24578378

Pubmed Central ID

  • 24578378

Electronic International Standard Serial Number (EISSN)

  • 1524-4636

International Standard Serial Number (ISSN)

  • 1079-5642

Digital Object Identifier (DOI)

  • 10.1161/ATVBAHA.114.303403

Language

  • eng