Combined administration of naked DNA vectors encoding VEGF and bFGF enhances tissue perfusion and arteriogenesis in ischemic hindlimb.
Few studies have examined in detail the combined effects of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) gene delivery on collateral development. Here, we evaluated the potential synergism of naked DNA vectors encoding VEGF and bFGF using a skeletal-muscle based ex vivo angiogenesis assay and compared tissue perfusion and limb loss in a murine model of hindlimb ischemia. In the ex vivo angiogenesis assay, the VEGF+bFGF combination group had a larger capillary sprouting area than those of the LacZ, VEGF, and bFGF groups. Consistent with these results, regional blood flow recovery on day 14 was also highest in the VEGF+bFGF combination group, followed by the bFGF, VEGF, and LacZ groups. The limb loss frequency was 0% in the combination group, whereas the limb loss frequencies of the other groups were 7-29%. The ischemic muscles of the combination group revealed evidence of increased angiogenesis and arteriogenesis and the upregulated expression of genes that may be associated with arteriogenesis, such as those for cardiac ankyrin repeat protein, early growth response factor-1, and transforming growth factor-beta1. Our study has implications for the development of a combined gene therapy for the vascular occlusive diseases.
Lee
Jung-Sun
JS
Cardiac and Vascular Center, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
Kim
Jeong-Min
JM
Kim
Koung Li
KL
Jang
Hyung-Suk
HS
Shin
In-Soon
IS
Jeon
Eun-Seok
ES
Suh
Wonhee
W
Byun
Jonghoe
J
Kim
Duk-Kyung
DK
D000818:Animals; D001158:Arteries / Q000254:growth & development*; D001483:Base Sequence; D004247:DNA / Q000008:administration & dosage*; D017931:DNA Primers; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D005822:Genetic Vectors; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D004247:DNA