Comparison of vascular endothelial growth factor and fibroblast growth factor-2 in a swine model of endothelial dysfunction

Boodhwani, Munir; Voisine, Pierre; Ruel, Marc; Sodha, Neel R.; Feng, Jun; Xu, Shu-Hua; Bianchi, Cesario; Sellke, Frank W.
April 2008
European Journal of Cardio-Thoracic Surgery;Apr2008, Vol. 33 Issue 4, p645
Academic Journal
Abstract: 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 (20–30kg), 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 (2μg; n =6), FGF-2 (100μg; 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.


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