ANGIOGENIC-INDUCED ENHANCEMENT OF COLLATERAL BLOOD-FLOW TO ISCHEMIC MYOCARDIUM BY VASCULAR ENDOTHELIAL GROWTH-FACTOR IN DOGS

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 for mation; however, the effects of VEGF on collateral flow to ischemic my ocardium are unknown. Methods and Results We studied the effect of VEG F on collateral blood flow in dogs subjected to gradual occlusion of t he left circumflex coronary artery (LCx). Beginning 10 days after plac ement of an LCx-constricting device, VEGF 45 mu g (n=9) or saline (n=1 2) was administered daily via an indwelling catheter in the distal LCx , at a point just beyond the occlusion. Treatment was maintained for 2 8 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 quan tified during chromonar-induced maximal vasodilation and expressed as a collateral zone/normal zone (CZ/NZ) ratio. Treatment with VEGF was a ssociated with a 40% increase in collateral blood flow (final CZ/NZ bl ood 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 mu m diameter) in the CZ (6.6+/-1.4 versus 3.5+/-0.7 vessels/ mm(2) in VE GF-treated and control dogs, respectively, P<.05). Conclusions We conc lude that intracoronary VEGF enhances the development of small coronar y arteries supplying ischemic myocardium, resulting in marked augmenta tion of maximal collateral blood flow delivery. These results demonstr ate the feasibility of pharmacological enhancement of collateral growt h and suggest a new therapeutic approach for the treatment of myocardi al ischemia.