title: AMP-Activated Protein Kinase α1 in Macrophages Promotes Collateral Remodeling and Arteriogenesis in Mice In Vivo.
abstract: AMP-activated protein kinase (AMPK), an energy and redox sensor, is activated in response to various cellular stresses, including hypoxia, nutrient deprivation, oxidative stress, and fluid shear stress at the site of vessel blockade. The activation of AMPK is involved in angiogenesis. However, it is unknown whether AMPK can influence arteriogenesis. Here, we demonstrate the contribution of macrophage AMPK to arteriogenesis and collateral remodeling and their underlying mechanisms in well-characterized in vivo and in vitro models.
  
  
  
  AMPKα1, AMPKα2 knockout and wild-type littermates underwent femoral artery ligation. Collateral arteriogenesis was monitored in wild-type, global AMPKα1 knockout, or macrophage-specific AMPKα1 knockout mice, with or without hindlimb ligation. Compared with wild-type mice with ligation, global AMPKα1 knockout mice displayed significant reduction in blood flow recovery and impaired remodeling of collateral arterioles. Similar impairments were observed in macrophage-specific AMPK α1 knockout mice after hindlimb ligation. Mechanistically, we found that AMPKα1 promotes the production of growth factors, such as transforming growth factor β, by directly phosphorylating the inhibitor of nuclear factor κB kinase alpha, resulting in an nuclear factor κB-dependent production of growth factors
  
  
  
  Our findings suggest a novel role for macrophage AMPKα1 in arteriogenesis and collateral remodeling and indicate that AMPKα1 activation might be beneficial for recovery from occlusive vascular disorders.
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.).
authors.forename: Huaiping
authors.initials: H
authors.lastname: Zhu
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.).
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.).
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.).
authors.forename: Junjie
authors.initials: J
authors.lastname: Xing
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.).
authors.forename: Cate
authors.initials: C
authors.lastname: Moriasi
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.).
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Dai
authors.affiliation: From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (H.Z., Z.L., C.M., X.D., M.-H.Z.); and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.Z., J.X.). mzou@gsu.edu.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003097:Collateral Circulation; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005838:Genotype; D057809:HEK293 Cells; D006614:Hindlimb; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008264:Macrophages / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D010766:Phosphorylation; D020127:Recovery of Function; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinases; NF-kappa B; macrophages; mice, knockout; transforming growth factor beta