Effects of recombinant eNOS gene expression on reactivity of small cerebral arteries

Resistance arteries are an important target for vascular gene therapy becau se they play a key role in the regulation of tissue blood flow. The present study was designed to determine the effects of recombinant endothelial (e) nitric oxide synthase (NOS) gene expression on vasomotor reactivity of sma ll brain stem arteries (internal diameter, 253 +/- 2.5 mu m) Arterial rings were exposed ex vivo to an adenoviral vector (10(9) and 10(10) plaque-form ing units/ml) encoding eNOS gene or beta-galactosidase gene. Twenty-four ho urs after transduction, vascular function was examined by isometric force s tudies. Transgene expression was evident mainly in adventitia. In arteries with endothelium transduced with eNOS gene but not with control beta-galact osidase gene, relaxations to bradykinin and substance P were significantly augmented. Removal of endothelium abolished relaxations to bradykinin and s ubstance P in control and beta-galactosidase arteries. However, in endothel ium-denuded arteries transduced with recombinant eNOS, bradykinin and subst ance P caused relaxations that were abolished in the presence of the NOS in hibitor N-G-nitro-L-arginine methyl eater. In control arteries, endothelium removal augmented relaxations to the nitric oxide donors sodium nitropruss ide and diethylamine NONOate. This augmentation was absent in eNOS gene-tra nsduced arteries without endothelium. Our results suggest that, in small br ain stem arteries, expression of recombinant eNOS increases biosynthesis of nitric oxide. Adventitia of small arteries is a good target for expression of recombinant eNOS. Genetically engineered adventitial cells may serve as a substitute source of nitric oxide in cerebral arteries with dysfunctiona l endothelium.