title: Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression.
abstract: 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.
  
  
  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.
authors.affiliation: From the Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH (J.D.B., U.M.C., M.S.W., E.G.T., R.B., P.E.D.); and Department of Aerospace and Mechanical Engineering, University of Notre Dame, IN (J.D.B.).
authors.forename: Joel D
authors.initials: JD
authors.lastname: Boerckel
authors.forename: Unnikrishnan M
authors.initials: UM
authors.lastname: Chandrasekharan
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Waitkus
authors.forename: Emily G
authors.initials: EG
authors.lastname: Tillmaand
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bartlett
authors.forename: Paul E
authors.initials: PE
authors.lastname: Dicorleto
mesh_terms: D000818:Animals; D001665:Binding Sites; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology*; D005091:Exons; D005786:Gene Expression Regulation; D006614:Hindlimb; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000235:genetics; D010766:Phosphorylation; D034622:RNA Interference; D012694:Serine; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D006657:Histones; D012694:Serine; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: MKP-1 phosphatase; angiogenesis effect