Comparison of vascular endothelial growth factor and fibroblast growth factor-2 in a swine model of endothelial dysfunction.
OBJECTIVE
Growth factor based angiogenesis, with or without cell therapy, is a promising therapeutic modality for patients with coronary artery disease. We compared the relative efficacies of surgically delivered vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in a swine model of hypercholesterolemia-induced endothelial dysfunction which captures many of the pathophysiologic abnormalities of human coronary disease.


METHODS
Yucatan mini-swine (20-30 kg), fed a high cholesterol diet (total 20 weeks), underwent circumflex ameroid placement to create chronic myocardial ischemia, followed three weeks later by perivascular administration of VEGF (2 microg; n=6), FGF-2 (100 microg; n=6), or placebo (n=7) in the ischemic territory. Normocholesterolemic animals (n=7) served as controls. Four weeks later, endothelial function, collateral-dependent perfusion, as well as myocardial protein and mRNA levels of angiogenic mediators were assessed.


RESULTS
Endothelial dysfunction was observed in all hypercholesterolemic animals as impaired microvessel relaxation in response to adenosine diphosphate and VEGF. VEGF administration improved baseline-adjusted collateral-dependent perfusion at rest (-0.03+/-0.05 vs -0.12+/-0.04, VEGF vs placebo, p=0.09), but FGF-2 delivery caused a significantly greater improvement in perfusion compared to either group (+0.15+/-0.03, p<0.05 vs HC-placebo and HC-VEGF) at rest. Molecular analysis revealed increased eNOS expression (135%+/-8%, p=0.03 vs placebo) in all growth factor treated animals and increased expression of FGF-2 receptor, FGFR1 (65+/-26%, p=0.04 vs placebo), in FGF-2 treated animals. No significant changes were demonstrated in other angiogenic mediators including Akt, Syndecan-4.


CONCLUSIONS
In the setting of hypercholesterolemic endothelial dysfunction, FGF-2 is more effective than VEGF at enhancing collateral-dependent perfusion and thus, may be a better candidate than VEGF for angiogenic therapy in patients with end-stage CAD.
Boodhwani
Munir
M
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
Voisine
Pierre
P
Ruel
Marc
M
Sodha
Neel R
NR
Feng
Jun
J
Xu
Shu-Hua
SH
Bianchi
Cesario
C
Sellke
Frank W
FW
D000818:Animals; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000503:physiopathology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications; D023421:Models, Animal; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013556:Swine, Miniature; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology / Q000627:therapeutic use*
D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2