LOCAL-DELIVERY OF VASCULAR ENDOTHELIAL GROWTH-FACTOR ACCELERATES REENDOTHELIALIZATION AND ATTENUATES INTIMAL HYPERPLASIA IN BALLOON-INJUREDRAT CAROTID-ARTERY

Background Most strategies designed to reduce restenosis by the use of pharmacological or biological reagents involve direct inhibition of v ascular smooth muscle cell (SMC) proliferation. Alternatively, SMC pro liferation might be indirectly inhibited if reendothelialization could be specifically facilitated at sites of balloon-induced arterial inju ry. Accordingly, we investigated the hypothesis that application of an endothelial cell (EC)-specific mitogen to a freshly denuded intimal s urface could accelerate reendothelialization and thereby attenuate int imal hyperplasia. Methods and Results The left carotid artery of 31 Sp rague-Dawley rats was subjected to balloon injury, after which 16 rats were treated with a 30-minute incubation with 100 mu g of vascular en dothelial growth factor (VEGF), an EC-specific mitogen. Control animal s (n=15) received a 30-minute incubation with 0.9% saline. At 2 weeks after balloon injury, carotid artery reendothelialization was markedly superior in the VEGF-treated group compared with the control group (1 4.59+/-1.12 versus 7.96+/-0.51 mm(2), P<.0005). The extent of reendoth elialization measured at 4 weeks after balloon injury remained superio r for arteries treated with VEGF (18.04+/-0.90 mm(2)) versus saline (1 3.42+/-0.84 mm(2), P<.005). Neointimal thickening was correspondingly attenuated to a statistically significant degree in arteries treated w ith VEGF versus the control group at both the 2-week and 4-week time p oints. Immunostaining for proliferating cell nuclear antigen (PCNA) di sclosed a threefold increase in PCNA-positive cells in the neointima o f control arteries versus VEGF-treated arteries at 2 weeks after injur y. Conclusions Application of VEGF, an EC-specific growth regulatory m olecule, may be effectively used in vivo to promote reendothelializati on and thereby indirectly attenuate neointimal thickening due to SMC p roliferation.