A VEGF trap inhibits the beneficial effect of bFGF on vasoreactivity in corporal tissues of hypercholesterolemic rabbits.
BACKGROUND
Hypercholesterolemia causes a decrease in normal corporal tissue vasoreactivity in a preclinical model of erectile dysfunction. Previous studies have shown that intracorporal injection (ICI) of basic fibroblast growth factor (bFGF) reverses some of the detrimental vasoreactivity effects of hypercholesterolemia and increases vascular endothelial growth factor (VEGF) expression.


OBJECTIVE
We sought to determine whether the beneficial effects of bFGF are VEGF-mediated.


METHODS
A total of 32 New Zealand white rabbits were fed a 1% cholesterol diet for 6 weeks and randomly divided into four groups (N = 8/group). Group 1 received a 2.5 microg bFGF ICI and 2.5 x 10(11) viral particle unit (vpu) of adenovirus encoding beta-galactosidase (Ad beta-gal) ICI, 10 days later. Group 2 received a 2.5 microg bFGF ICI and 2.5 x 10(11) vpu of adenovirus encoding soluble VEGF receptor (VEGFR) (AdsVEGFR, a VEGF trap) ICI, 10 days later. Group 3 received phosphate buffered saline solution (PBS) ICI and 2.5 x 10(11) vpu Ad beta-gal ICI, 10 days later. Group 4 received PBS ICI and 2.5 x 10(11) vpu AdsVEGFR ICI, 10 days later.


METHODS
The corpus cavernosum was harvested for vasoreactivity studies 10 days post viral injection. The effective dose of 50% maximum relaxation was determined. VEGF levels were assessed by enzyme-linked immunosorbent assay. Total and phosphorylated Akt and endothelial nitric oxide were analyzed by Western blot.


RESULTS
Endothelium-dependent vasoreactivity was significantly greater in Group 1 vs. all other groups. The VEGF trap eliminated the beneficial effects of bFGF on endothelium-dependent vasoreactivity and decreased Akt and nitric oxide phosphorylation.


CONCLUSIONS
These data demonstrate that VEGF activity contributes much of the therapeutic modulation of bFGF-mediated vasoreactivity in corporal tissue.
Xie
Donghua
D
Division of Cardiovascular Medicine and the Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Findley
Clarence M
CM
Greenfield
Jason M
JM
Pippen
Anne M
AM
Kontos
Christopher D
CD
Donatucci
Craig F
CF
Annex
Brian H
BH
D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D006937:Hypercholesterolemia / Q000503:physiopathology*; D018783:Impotence, Vasculogenic / Q000503:physiopathology*; D007273:Injections, Intramuscular; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010413:Penis / Q000098:blood supply*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt