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Synergistic effect of vascular endothelial growth factor and granulocyte colony‐stimulating factor double gene therapy in mouse limb ischemia
Author(s) -
Sacramento Chester Bittencourt,
da Silva Flavia Helena,
Nardi Nance Beyer,
Yasumura Eduardo Gallatti,
BaptistaSilva José Carlos Costa,
Beutel Abram,
de Campos Ruy Ribeiro,
de Moraes Jane Zveiter,
Junior Hamilton Silva,
Samoto Vivian Yochiko,
Borojevic Radovan,
Han Sang Won
Publication year - 2010
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1434
Subject(s) - vascular endothelial growth factor , ischemia , genetic enhancement , granulocyte colony stimulating factor , granulocyte , medicine , growth factor , hindlimb , fibrosis , vascular endothelial growth factor a , biology , endocrinology , gene , vegf receptors , chemotherapy , biochemistry , receptor
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.