BACKGROUND Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is angiogenic in vitro and in vivo. It has been hypothesized that VEGF plays a role in myocardial collateral formation; however, the effects of VEGF on collateral flow to ischemic myocardium are unknown. METHODS AND RESULTS We studied the effect of VEGF on collateral blood flow in dogs subjected to gradual occlusion of the left circumflex coronary artery (LCx). Beginning 10 days after placement of an LCx-constricting device, VEGF 45 micrograms (n = 9) or saline (n = 12) was administered daily via an indwelling catheter in the distal LCx, at a point just beyond the occlusion. Treatment was maintained for 28 days. Collateral blood flow was determined with microspheres 7 days before treatment, immediately before treatment (day 0), and 7, 14, 21, and 28 days into the treatment period. Collateral blood flow was quantified during chromonar-induced maximal vasodilation and expressed as a collateral zone/normal zone (CZ/NZ) ratio. Treatment with VEGF was associated with a 40% increase in collateral blood flow (final CZ/NZ blood flow ratios of 0.49 +/- 0.06 and 0.35 +/- 0.02 in the VEGF-treated and control groups, respectively, P = .0037) as well as an 89% increase in the numerical density of intramyocardial distribution vessels (> 20 microns diameter) in the CZ (6.6 +/- 1.4 versus 3.5 +/- 0.7 vessels/mm2 in VEGF-treated and control dogs, respectively, P < .05). CONCLUSIONS We conclude that intracoronary VEGF enhances the development of small coronary arteries supplying ischemic myocardium, resulting in marked augmentation of maximal collateral blood flow delivery. These results demonstrate the feasibility of pharmacological enhancement of collateral growth and suggest a new therapeutic approach for the treatment of myocardial ischemia.

Short-term treatment with bFGF enhanced collateral development without increasing neointimal accumulation at sites of vascular injury. Although VEGF did not increase collateral development as administered in this study, it significantly exacerbated neointimal accumulation. These data provide support for the clinical investigation of bFGF in selected patients with ischemic heart disease.

Basic fibroblast growth factor (FGF) is a multifunctional peptide that may play an integral role in angiogenesis associated with coronary collateral formation and myocardial infarct healing. We sought to determine the effects of exogenously administered basic FGF on collateral blood flow to ischemic myocardium. Ameroid constrictors were used to cause gradual occlusion of the left circumflex coronary artery in dogs. Basic FGF (110 micrograms, n = 9) or saline (n = 12) was given as a daily bolus injection directly into the collateral-dependent zone, beginning 10 days after placement of the Ameroid and continuing for 28 days. Collateral flow was assessed weekly as the ratio of collateral to normal zone (CZ/NZ) blood flow during maximal pharmacologically induced coronary vasodilation. The CZ/NZ increased in both treated and control dogs as a function of time; however, transmural collateral flow in basic FGF-treated dogs significantly exceeded that of control dogs by the second week of treatment. Final CZ/NZ blood flow ratios were 0.49 +/- 0.05 and 0.35 +/- 0.02 in the treated and control groups, respectively (means +/- SE, P = 0.0002). Treatment with basic FGF was also associated with significant increases in the numerical density of distribution vessels and endothelial cell DNA synthesis within the CZ. We also found that basic FGF had acute effects as a coronary vasodilator. Thus exogenous administration of basic FGF enhances maximal collateral blood flow in dogs with myocardial ischemia secondary to single-vessel coronary occlusion, an effect that is likely mediated through the direct angiogenic effects of the peptide, although its acute vasodilatory effects may also play a role.