Vascular endothelial growth factor (VEGF165) plus basic fibroblast growth factor (bFGF) producing cells induce a mature and stable vascular network--a future therapy for ischemically challenged tissue.
BACKGROUND
Vascular endothelial growth factor (VEGF)(165) induces formation of immature blood vessels with increased permeability. In this study, we used a cell-based gene-transfer model of fibroblasts to investigate the effects of a combined in vivo treatment consisting of the VEGF165 and basic fibroblast growth factor (bFGF) proteins on ischemic and non-ischemic tissues.


METHODS
After controlled in vitro adenoviral transfection we transplanted fibroblasts into either healthy tissue, or into an ischemic skin flap model at different tissue locations and at different time points. Subsequent protein expression and angiogenic effects were measured using ELISA, PCR, immunohistology, planimetry, and microangiography.


RESULTS
Transfected fibroblasts temporarily produced VEGF(165) and bFGF. After transdermal implantation we found an up-regulation of genes encoding for both factors in tissue samples. The combined transplantation of VEGF(165) and bFGF modified cells increased the number of sm-actin+/CD31+ blood vessels and reduced necrosis by 25%. The number of functional blood vessels increased over a period of 168 d even in healthy tissue.


CONCLUSIONS
We achieved stable vessel growth in healthy tissue by inducing a temporary overexpression of VEGF(165) and bFGF and improved the survival of ischemic tissue. One possible mechanism for the latter observation is the stabilization of VEGF(165)-induced hyperpermeable vessels by a bFGF-mediated pericytial recruitment of smooth muscle cells.
Spanholtz
Timo A
TA
Department of Plastic and Hand Surgery, Burn Care Center, Institute for Research in Operative Medicine (IFOM), University Hospital Witten/Herdecke, Campus Cologne, Germany. timo@spanholtz.net
Theodorou
Panagiotis
P
Holzbach
Thomas
T
Wutzler
Sebastian
S
Giunta
Riccardo E
RE
Machens
Hans-Guenther
HG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival / Q000502:physiology; D007511:Ischemia / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply; D013524:Surgical Flaps / Q000098:blood supply; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D016222:Fibroblast Growth Factor 2