Synergistic effect of vascular endothelial growth factor and granulocyte colony-stimulating factor double gene therapy in mouse limb ischemia

Background Vascular endothelial growth factor (VEGF) has mostly been tested to treat ischemic diseases, although the outcomes obtained are not satisfactory. Our hypothesis is that the local transient expression of VEGF and stem cell mobilizer granulocyte colony‐stimulating factor (G‐CSF) genes in is...

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Published in:The journal of gene medicine 2010-03, Vol.12 (3), p.310-319
Main Authors: Sacramento, Chester Bittencourt, da Silva, Flavia Helena, Nardi, Nance Beyer, Yasumura, Eduardo Gallatti, Baptista-Silva, José Carlos Costa, Beutel, Abram, de Campos, Ruy Ribeiro, de Moraes, Jane Zveiter, Junior, Hamilton Silva, Samoto, Vivian Yochiko, Borojevic, Radovan, Han, Sang Won
Format: Article
Language:English
Subjects:
angiogenesis
Animals
electroporation
Extremities - blood supply
GCSF
Gene therapy
Genetic Therapy - methods
Granulocyte Colony-Stimulating Factor - genetics
Ischemia - blood
Ischemia - etiology
Ischemia - therapy
limb ischemia
Male
Mice
Mice, Inbred BALB C
Muscle, Skeletal - blood supply
Muscle, Skeletal - physiology
Neovascularization, Physiologic - genetics
Peripheral Vascular Diseases - complications
Peripheral Vascular Diseases - therapy
Regeneration - genetics
Vascular Endothelial Growth Factor A - genetics
VEGF
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Summary:Background Vascular endothelial growth factor (VEGF) has mostly been tested to treat ischemic diseases, although the outcomes obtained are not satisfactory. Our hypothesis is that the local transient expression of VEGF and stem cell mobilizer granulocyte colony‐stimulating factor (G‐CSF) genes in ischemic limbs can complement their activities and be more efficient for limb recovery. Methods Limb ischemia was surgically induced in mice and 50 µg of VEGF and/or G‐CSF genes were locally transferred by electroporation. After 3–4 weeks, evidence of necrosis by visual inspection, capillary density, muscle mass, muscle force and hematopoietic cell mobilization were evaluated. Results After 4 weeks, 70% and 90% of the animals of the ischemic group (IG) and VEGF‐treated group (VG), respectively, presented limb necrosis, in contrast to only 10% observed in the group of mice treated with both VEGF and G‐CSF genes (VGG). Recovery of muscle mass and muscle force was higher than 60% in the VGG compared to the non‐ischemic group. The mobilization of Sca1+ cells and neutrophils was also higher in the VGG, which may explain the lower level of necrosis observed in this group (22%, in contrast to 70% in the IG). Capillary density and degree of fibrosis were determined in weeks 3 and 4, and also showed a clear benefit as a result of the use of the G‐CSF and VEGF genes together. Conclusions Gene therapy using VEGF and G‐CSF demonstrated a synergistic effect promoting vessel and tissue repair in mouse hind limb ischemia. Copyright © 2010 John Wiley & Sons, Ltd.
ISSN:1099-498X
1521-2254
1521-2254
DOI:10.1002/jgm.1434