title: MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization.
abstract: BACKGROUND
  Adaptive neovascularization after arterial occlusion is an important compensatory mechanism in cardiovascular disease and includes both the remodeling of pre-existing vessels to collateral arteries (arteriogenesis) and angiogenic capillary growth. We now aimed to identify regulatory microRNAs involved in the modulation of neovascularization after femoral artery occlusion in mice.
  
  
  RESULTS
  Using microRNA-transcriptome analysis, we identified miR-155 as a downregulated microRNA during hindlimb ischemia. Correspondingly, inhibition of miR-155 in endothelial cells had a stimulatory effect on proliferation and angiogenic tube formation via derepression of its direct target gene angiotensin II type 1 receptor. Surprisingly, miR-155-deficient mice showed an unexpected phenotype in vivo, with a strong reduction of blood flow recovery after femoral artery ligation (arteriogenesis) dependent on the attenuation of leukocyte-endothelial interaction and a reduction of proarteriogenic cytokine expression. Consistently, miR-155-deficient macrophages exhibit a specific alteration of the proarteriogenic cytokine expression profile, which is partly mediated by the direct miR-155 target gene SOCS-1.
  
  
  CONCLUSIONS
  Our data demonstrate that miR-155 exerts an antiangiogenic but proarteriogenic function in the regulation of neovascularization via the suppression of divergent cell-specific target genes and that its expression in both endothelial and bone marrow-derived cells is essential for arteriogenesis in response to hindlimb ischemia in mice.
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Franziska
authors: F
authors: Pankratz
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Xavier
authors: X
authors: Bemtgen
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Robert
authors: R
authors: Zeiser
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Franziska
authors: F
authors: Leonhardt
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Sheena
authors: S
authors: Kreuzaler
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Ingo
authors: I
authors: Hilgendorf
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Christian
authors: C
authors: Smolka
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Thomas
authors: T
authors: Helbing
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Imo
authors: I
authors: Hoefer
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Jennifer S
authors: JS
authors: Esser
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Max
authors: M
authors: Kustermann
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Martin
authors: M
authors: Moser
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.).
authors: Christoph
authors: C
authors: Bode
authors: From Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany (F.P., X.B., S.K., I.Hi., C.S., T.H., J.S.E., M.K., M.M., C.B., S.G.); Department of Biology, Albert-Ludwigs-University, Freiburg, Germany (F.P., F.L.); Department of Hematology and Oncology, University Hospital Freiburg, Germany (R.Z., F.L.); and Experimental Cardiology Laboratory, University Medical Center Utrecht, The Netherlands (I.Ho.). sebastian.grundmann@universitaets-herzzentrum.de.
authors: Sebastian
authors: S
authors: Grundmann
mesh_terms: D000818:Animals; D001158:Arteries / Q000503:physiopathology; D001483:Base Sequence; D002465:Cell Movement; D003097:Collateral Circulation / Q000235:genetics*; D016207:Cytokines / Q000502:physiology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000503:physiopathology; D005263:Femoral Artery; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply*; D061307:Human Umbilical Vein Endothelial Cells; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007511:Ischemia / Q000235:genetics*; D017078:Laser-Doppler Flowmetry; D007962:Leukocytes / Q000502:physiology; D008026:Ligation; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D044140:Receptor, Angiotensin, Type 1; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: angiogenesis effect; microRNAs