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

Department of Biochemistry and Biophysics, 1st School of Medicine, II University of Naples, 80138 Naples, Italy.
Atherosclerosis (Impact Factor: 3.99). 10/2009; 209(2):403-14. DOI: 10.1016/j.atherosclerosis.2009.10.022
Source: PubMed

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

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Available from: Lucio Pastore, Apr 26, 2014
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    • "Third, we assessed the in vivo neovascularization capacity of FOXO4KD-EPCs in the ischemic limbs of rats without atherosclerotic risk factors. It has been reported that hindlimb ischemia induction in rodents with atherosclerotic risk factors further increased oxidative stress in the plasma and ischemic limb tissue [24]–[26]. Accordingly, in the ischemic limbs of rodents with atherosclerotic risk factors we may not be able to obtain the same neovascularization by FOXO4KD-EPCs as we did in this study. Forth, we did not perform this study using healthy volunteer-derived FOXO4KD-EPCs in vivo. "
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    • "This process could have a great therapeutic impact. A recent study reported the effects of intravenous injection of bone marrow cells (BMCs) and HS, supplemented with 1.0% vitamin E, 0.05% vitamin C, and 6% l-arginine, into the ischemic hindlimb of ApoE−/− diabetic and nondiabetic mice [47]. Blood flow was monitored by a laser Doppler blood flow meter, and capillary density was determined in sections of the adductor and semimembranous muscles with an anti-CD31 antibody. "
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