Therapeutic angiogenesis in diabetic apolipoprotein E-deficient mice using bone marrow cells, functional hemangioblasts and metabolic intervention

Maria Luisa Balestrieri, Shi-Jiang Lu, Filomena de Nigris, Alfonso Giovane, Sharon Williams-Ignarro, Francesco Paolo D'Armiento, Qiang Feng, Carmela Fiorito, Gianluca Testa, Lucio Pastore, Francesco Cacciatore, Francesco Paolo Mancini, Luigi Servillo, Gaetano De Rosa, Caterina Pagliarulo, Monica Rienzo, Pellegrino Biagio Minucci, Bartolomeo Farzati, Francesco Salvatore, Franco RengoLouis Joseph Ignarro, Antonio Giordano, Andrew Baker, Robert Lanza, Claudio Napoli

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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/INTERPRETATION: Intravenous autologous BMC and HS intervention together with MT increased therapeutic angiogenesis in the ApoE(-/-) diabetic mouse hindlimb.

Original languageEnglish
Pages (from-to)403-14
Number of pages12
Issue number2
Publication statusPublished - Apr 2010

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Apolipoproteins E
  • Arginine
  • Ascorbic Acid
  • Bone Marrow Transplantation
  • Diabetes Mellitus, Experimental
  • Hemangioblasts
  • Hindlimb
  • Ischemia
  • Mice
  • Neovascularization, Physiologic
  • Peripheral Vascular Diseases
  • Regional Blood Flow
  • Vitamin E


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