VEGF Gene Transfer Reduces Intimal Thickening via Increased Production of Nitric Oxide in Carotid Arteries

Publisher Website
Google Scholar
Abstract
Thickening of the arterial intima and smooth muscle cell (SMC) proliferation remain major problems after vascular surgery and other types of vascular manipulations. We studied the effect of endothelial cell (EC)-specific vascular endothelial growth factor (VEGF) gene transfer on the thickening of the intima using a silicone collar inserted around carotid arteries that acted both as the agent that caused intimal SMC growth and as a reservoir for the transfected gene. The model preserved EC integrity and permitted direct extravascular gene transfer without any intravascular manipulation. Compared to β-galactosidase (lacZ)-transfected control arteries, plasmid/liposome-mediated VEGF gene transfer significantly reduced intimal thickening 1 week after the gene transfer. Administration to the experimental animals of the nitric oxide (NO) synthase inhibitor L-NAME abolished the difference in intimal thickening between VEGF and lacZ-transfected arteries. Furthermore, VEGF caused NO release from cultured human umbilical vein EC. It is concluded that extravascular VEGF gene transfer attenuates intimal growth and could be useful for the prevention of intimal thickening during vascular surgery. Our results further suggest that VEGF may reduce SMC proliferation via a mechanism that involves VEGF-induced NO production from the endothelium. Intimal thickening remains a major problem after vascular manipulations. Extravascular delivery of vascular endothelial growth factor (VEGF) plasmid/liposome complexes was shown to reduce intimal thickening in rabbit carotid arteries 1 week after the gene transfer. Administration to the experimental animals of the nitric oxide (NO) synthase inhibitor L-NAME abolished beneficial effects of VEGF gene transfer. We also showed that VEGF induced a time- and concentration-dependent release of NO from cultured endothelial cells in vitro. We conclude that VEGF gene transfer reduces intimal thickening via a mechanism that involves VEGF-induced NO production from the endothelium.