title: PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle.
abstract: BACKGROUND
  Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle.
  
  
  OBJECTIVE
  To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.
  
  
  RESULTS
  Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease.
  
  
  CONCLUSIONS
  PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Raghuram
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Cholsoon
authors.initials: C
authors.lastname: Jang
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Nagy
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Patten
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Goyal
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Mun Chun
authors.initials: MC
authors.lastname: Chan
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Laura X
authors.initials: LX
authors.lastname: Liu
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Aihua
authors.initials: A
authors.lastname: Jiang
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Spokes
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: David
authors.initials: D
authors.lastname: Beeler
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Harold
authors.initials: H
authors.lastname: Dvorak
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.affiliation: From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. zarany@bidmc.harvard.edu.
authors.forename: Zolt
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C506896:Spp1 protein, mouse; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D053495:Osteopontin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: PGC-1alpha protein, mouse; angiogenesis effect; cytokines; gene action regulation; genetic therapy; intercellular signaling peptides and proteins; macrophages; muscle; osteopontin; peripheral arterial disease; skeletal