title: Polymerase δ-interacting protein 2 promotes postischemic neovascularization of the mouse hindlimb.
abstract: OBJECTIVE
  Collateral vessel formation can functionally compensate for obstructive vascular lesions in patients with atherosclerosis. Neovascularization processes are triggered by fluid shear stress, hypoxia, growth factors, chemokines, proteases, and inflammation, as well as reactive oxygen species, in response to ischemia. Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates focal adhesion turnover and vascular smooth muscle cell migration and modifies extracellular matrix composition. We, therefore, tested the hypothesis that loss of Poldip2 impairs collateral formation.
  
  
  RESULTS
  The mouse hindlimb ischemia model has been used to understand mechanisms involved in postnatal blood vessel formation. Poldip2(+/-) mice were subjected to femoral artery excision, and functional and morphological analysis of blood vessel formation was performed after injury. Heterozygous deletion of Poldip2 decreased the blood flow recovery and spontaneous running activity at 21 days after injury. H2O2 production, as well as the activity of matrix metalloproteinases-2 and -9, was reduced in these animals compared with Poldip2(+/+) mice. Infiltration of macrophages in the peri-injury muscle was also decreased; however, macrophage phenotype was similar between genotypes. In addition, the formation of capillaries and arterioles was impaired, as was angiogenesis, in agreement with a decrease in proliferation observed in endothelial cells treated with small interfering RNA against Poldip2. Finally, regression of newly formed vessels and apoptosis was more pronounced in Poldip2(+/-) mice.
  
  
  CONCLUSIONS
  Together, these results suggest that Poldip2 promotes ischemia-induced collateral vessel formation via multiple mechanisms that likely involve reactive oxygen species-dependent activation of matrix metalloproteinase activity, as well as enhanced vascular cell growth and survival.
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: Angélica M
authors.initials: AM
authors.lastname: Amanso
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: Bernard
authors.initials: B
authors.lastname: Lassègue
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: Giji
authors.initials: G
authors.lastname: Joseph
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: Natalia
authors.initials: N
authors.lastname: Landázuri
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: James S
authors.initials: JS
authors.lastname: Long
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: Daiana
authors.initials: D
authors.lastname: Weiss
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.).
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: From the Department of Medicine, Division of Cardiology (A.M.A., B.L., G.J., J.S.L., D.W., W.R.T., K.K.G.) and The Wallace H. Coulter Department of Biomedical Engineering (W.R.T.), Emory University, Atlanta, GA; and Department of Medicine, Division of Cardiology, Atlanta VA Medical Center, GA (W.R.T.). kgriend@emory.edu.
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D003097:Collateral Circulation; D004195:Disease Models, Animal; D006579:Heterozygote; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020127:Recovery of Function; D012039:Regional Blood Flow; D013997:Time Factors; D014162:Transfection
chemical_list: D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C473592:POLDIP2 protein, human; C514737:mitogenin 1 protein, mouse; D006861:Hydrogen Peroxide; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: NADPH oxidase; apoptosis; ischemia; metalloproteases; neovascularization