title: Therapeutic angiogenesis in diabetic apolipoprotein E-deficient mice using bone marrow cells, functional hemangioblasts and metabolic intervention.
abstract: OBJECTIVE
  Peripheral arterial disease (PAD) is a major health problem especially when associated to concomitant diabetes and hypercholesterolemia. Hyperglycemia with an overwhelming generation of oxygen radicals and formation of glycation end-products exacerbates oxidation-sensitive mechanisms activated by tissue ischemia. Administration of autologous bone marrow cells (BMC) is an increasing notable intervention to induce therapeutic angiogenesis, ameliorated by metabolic intervention (MT). Recently, hemangioblasts (HS) with functional properties were isolated.
  
  
  METHODS
  The effects of integrate regimen with intravenous BMC, HS, and MT (1.0% vitamin E, 0.05% vitamin C, and 6% l-arginine) were examined in the ischemic hindlimb of ApoE(-/-) diabetic and non-diabetic. Blood flow ratio was monitored by use of a laser Doppler blood flowmeter. Capillary density was determined in sections of the adductor and semimembranous muscles with antibody against CD31.
  
  
  RESULTS
  BMC or HS alone, and BMC plus HS increased blood flow and capillary densities and decreased interstitial fibrosis. These effects were amplified by additional MT, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress and macrophage infiltration. Investigation of molecular mechanisms in bone marrow (BM)-derived progenitor cells from mice revealed that BMC therapy and, more consistently, in combination with MT ameliorated functional activity via decreased cellular senescence and increased telomerase and chemokine CXCR4 activities. Telomerase activity was also increased by HS alone or HS+MT and, more consistently, by BMC+HS alone or in combination with MT.
  
  
  CONCLUSIONS
  Intravenous autologous BMC and HS intervention together with MT increased therapeutic angiogenesis in the ApoE(-/-) diabetic mouse hindlimb.
authors.affiliation: Department of Biochemistry and Biophysics, 1st School of Medicine, II University of Naples, 80138 Naples, Italy. marialuisa.balestrieri@unina2.it
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Balestrieri
authors.forename: Shi-Jiang
authors.initials: SJ
authors.lastname: Lu
authors.forename: Filomena
authors.initials: F
authors.lastname: de Nigris
authors.forename: Alfonso
authors.initials: A
authors.lastname: Giovane
authors.forename: Sharon
authors.initials: S
authors.lastname: Williams-Ignarro
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: D'Armiento
authors.forename: Qiang
authors.initials: Q
authors.lastname: Feng
authors.forename: Carmela
authors.initials: C
authors.lastname: Fiorito
authors.forename: Gianluca
authors.initials: G
authors.lastname: Testa
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.forename: Francesco
authors.initials: F
authors.lastname: Cacciatore
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Mancini
authors.forename: Luigi
authors.initials: L
authors.lastname: Servillo
authors.forename: Gaetano
authors.initials: G
authors.lastname: De Rosa
authors.forename: Caterina
authors.initials: C
authors.lastname: Pagliarulo
authors.forename: Monica
authors.initials: M
authors.lastname: Rienzo
authors.forename: Pellegrino Biagio
authors.initials: PB
authors.lastname: Minucci
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Farzati
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.forename: Franco
authors.initials: F
authors.lastname: Rengo
authors.forename: Louis Joseph
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Andrew
authors.initials: A
authors.lastname: Baker
authors.forename: Robert
authors.initials: R
authors.lastname: Lanza
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001120:Arginine / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D055018:Hemangioblasts / Q000637:transplantation*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000628:therapy; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016491:Peripheral Vascular Diseases / Q000628:therapy*; D012039:Regional Blood Flow; D014810:Vitamin E / Q000627:therapeutic use
chemical_list: D001057:Apolipoproteins E; D014810:Vitamin E; D001120:Arginine; D001205:Ascorbic Acid