Evaluation of different approaches to enhancing arteriogenesis using isolated monocytes and GM-CSF treatment in an ischemic mouse hind limb model
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Arteriogenesis, the growth of collateral arteries as a compensatory mechanism afterocclusion of a major artery, is a complex process in which peripheral blood cells have beenproposed to be involved. This study was concentrated on the role of monocytes, effects ofdifferent monocyte concentrations in the blood and effects of monocyte pre-treatment withspecific substances on the enhancement of collateral artery growth.For this purpose, a mouse ischemic hind limb model was established on the BALB/cgenetic background. After acute femoral artery occlusion, mice received intravenousinjections of monocytes in several concentrations, isolated from donor littermates using a cellsorter. Moreover, we pre-treated monocytes with a synthetic prostaglandin (Cicaprost) or withgranulocyte-macrophage colony-stimulating factor (GM-CSF). We also evaluated if treatmentof operated mice with GM-CSF alone could enhance collateral artery growth and if acombination of monocyte injections with GM-CSF had a synergistic effect. Pedal blood flowrecovery in mice was measured using the laser Doppler imaging technique immediately afteroperation and on postoperative day 3, 7, 14 and 21. Moreover, pedal hemoglobin oxygensaturation was estimated at the same time points. Functional recovery of the foot movementwas observed during the whole trial period. On the day 21 after the operation, post-mortemangiogramms were performed and adductor muscles were harvested for the morphometricalanalysis. The hemodynamic data showed that injection of monocytes had a concentrationdependenteffect in enhancing of blood flow recovery in the operated foot. Seven days afterfemoral artery ligature, the blood flow recovery (right-to-left ratio) was only 0.21 ± 0.02 incontrol mice and significantly higher in mice which had obtained monocyte injections (0.30 ±0.04 in mice with 2x105 monocytes injected, p<0.05 and 0.33 ± 0.04 in mice with 3x105monocytes injected, p<0.01). Morphometrical analysis of adductor muscles of operated andnon-operated hind limbs showed that total collateral area ratio, which was obtained as aparameter to estimate collateral artery size, increased markedly in monocyte-treated micecompared to controls (2.37 ± 0.12 in mice with 2x105 monocytes injected; p<0.01 and 2.66 ±0.12 in mice with 3x105 monocytes injected; p<0.01 vs. 1.88 ± 0.08 in controls). Pretreatmentof monocytes with Cicaprost or GM-CSF did not enhance their arteriogenicproperties. Administration of GM-CSF via intraperitoneal injections did not enhance theblood flow recovery, however the combination of GM-CSF and monocyte injections had a moderate synergistic effect reflected in blood flow measurements (R/L ratio on day 7 was0.40 ± 0.05 which was the highest ratio of all experimental groups of animals; p<0.01), aswell as in morphometrical analysis of adductor muscles (total collateral area ratio was 3.32 ±0.14; p<0.01)Our results show that monocytes/macrophages play a crucial role in enhancement ofcollateral artery growth. In addition, a combination of GM-CSF treatment and monocyteinjections allows administration of smaller concentrations of therapeutics and results in asuperior blood flow recovery. Our study suggests a possibility of using cellular approaches forthe treatment of vascular occlusive diseases.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler 2006