title: COMP-angiopoietin-1 recovers molecular biomarkers of neuropathy and improves vascularisation in sciatic nerve of ob/ob mice.
abstract: BACKGROUND
  Leptin-deficient ob/ob mice are a model of type 2 diabetes induced peripheral neuropathy. Ob/ob mice exhibit obesity, insulin resistance, hyperglycaemia, and alterations of peripheral nerve fibres and endoneural microvessels. Here we test the hypothesis that cartilage oligomeric matrix protein (COMP)-Ang-1, a soluble and stabile form of Ang-1 which promotes angiogenesis and nerve growth, improves regeneration of nerve fibres and endoneural microvessels in ob/ob mice.
  
  
  RESULTS
  COMP-Ang-1 (100 ng/ml) or NaCl were intraperitoneally (i.p.) injected into male (N = 184), 3-month old, ob/ob or ob/+ mice for 7 and 21 days. We measured expression of Nf68, GAP43, Cx32, Cx26, Cx43, and TNFα in sciatic nerves using Western blot analysis. To investigate the inflammation in sciatic nerves, numbers of macrophages and T-cells were counted after immunofluorescence staining. In ultrathin section, number of myelinated/non-mylinated nerve fibers, g-ratio, the thickness of Schwann cell basal lamina and microvessel endothelium were investigated. Endoneural microvessels were reconstructed with intracardial FITC injection. Treatment with COMP-Ang-1 over 21 days significantly reduced fasting blood glucose and plasma cholesterol concentrations compared to saline treated ob/ob mice. In addition, COMP-Ang-1 treatment: 1) up-regulated expression of Nf68 and GAP43; 2) improved expression of gap junction proteins including connexin 32 and 26; 3) suppressed the expression of TNFα and Cx43 and 4) led to decreased macrophage and T-cell infiltration in sciatic nerve of ob/ob mice. The significant changes of sciatic nerve ultrastructure were not observed after 21-day long COMP-Ang-1 treatment. COMP-Ang-1 treated ob/ob mice displayed regeneration of small-diameter endoneural microvessels. Effects of COMP-Ang-1 corresponded to increased phosphorylation of Akt and p38 MAPK upon Tie-2 receptor.
  
  
  CONCLUSIONS
  COMP-Ang-1 recovers molecular biomarkers of neuropathy, promotes angiogenesis and suppresses inflammation in sciatic nerves of ob/ob mice suggesting COMP-Ang-1 as novel treatment option to improve morphologic and protein expression changes associated with diabetic neuropathy.
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany. Joanna.Kosacka@medizin.uni-leipzig.de
authors.forename: Joanna
authors.initials: J
authors.lastname: Kosacka
authors.forename: Marcin
authors.initials: M
authors.lastname: Nowicki
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.forename: Matthias
authors.initials: M
authors.lastname: Kern
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Heike
authors.initials: H
authors.lastname: Serke
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
mesh_terms: D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D017630:Connexins / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D012584:Sciatic Nerve / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C515576:COMP-Ang1 fusion protein; D017630:Connexins; D011993:Recombinant Fusion Proteins; D002784:Cholesterol; D042787:Receptor, TIE-2; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases