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

Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States

Received 27 August 2007; received in revised form 29 November 2007; accepted 11 December 2007.

^_* Corresponding author. Address: Division of Cardiothoracic Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, 110 Francis Street, LMOB 2A, Boston, MA 02215, United States. Tel.: +1 617 632 8385; fax: +1 617 632 8387. (Email: fsellke{at}caregroup.harvard.edu).

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 µg; n = 6), FGF-2 (100 µg; 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.

Key Words: Endothelial dysfunction • Vascular endothelial growth factor • Fibroblast growth factor • Myocardial ischemia • Angiogenesis • Molecular biology

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				D. J. Chambers Editorial comment Eur. J. Cardiothorac. Surg., April 1, 2008; 33(4): 651 - 652. [Full Text] [PDF]