Arteriosclerosis, thrombosis, and vascular biology, 2014-05, Vol.34 (5), p.1020
2014
Details
- Autor(en) / Beteiligte
- Titel
- Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression
- Ist Teil von
- Arteriosclerosis, thrombosis, and vascular biology, 2014-05, Vol.34 (5), p.1020
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1524-4636DOI: 10.1161/ATVBAHA.114.303403Titel-ID: cdi_pubmed_primary_24578378
- Format
- –
- Schlagworte
- Animals, Binding Sites, Cell Movement, Cell Proliferation, Cells, Cultured, Chemokine CX3CL1 - administration & dosage, Chemokine CX3CL1 - genetics, Chemokine CX3CL1 - metabolism, Disease Models, Animal, Dual Specificity Phosphatase 1 - deficiency, Dual Specificity Phosphatase 1 - genetics, Dual Specificity Phosphatase 1 - metabolism, Endothelial Cells - enzymology, Exons, Gene Expression Regulation, Hindlimb, Histones - metabolism, Human Umbilical Vein Endothelial Cells - enzymology, Humans, Ischemia - enzymology, Ischemia - genetics, Ischemia - physiopathology, Ischemia - therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal - blood supply, Neovascularization, Physiologic - genetics, Phosphorylation, RNA Interference, Serine, Signal Transduction, Time Factors, Transfection