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First-generation, E1-deleted adenoviral vectors (E1-AV) can transduce the vascular endothelium with high efficiency, but their use is limited by the resulting acute endothelial injury and the long-term development of intimal hyperplasia. To reduce the impact of viral proteins on the gene-modified cells, a second-generation adenoviral vector with an additional pair of deletions in the E4 region was developed. To determine whether this E1/E4-AV vector would be useful for vascular gene transfer, we directly compared the efficiency of gene transfer to uninjured rabbit carotid arteries using either an E1/E4-AV or an E1-AV vector encoding beta-galactosidase. Both vectors efficiently transduced vascular endothelium; however, the E1/E4-AV vector gene-modified vessels showed higher beta-galactosidase expression 10 days after gene transfer. Importantly, the E1/E4-AV vector produced substantially less endothelial cell activation, less inflammation, and reduced neointimal hyperplasia compared with the E1-AV vector-treated vessels. The E1-AV vector-transduced vessels also demonstrated significantly impaired endothelium-dependent relaxation whereas the E1/E4-AV vector did not impact vasomotor function, even at doses of virus in 5-fold excess of the amount required for >90% transduction of the endothelium. We conclude that the E1/E4-AV vector is superior to the E1-AV vector for vascular gene therapy because of the prolonged transgene expression, reduced vascular inflammation, reduced intimal hyperplasia, and maintenance of normal vasomotor function.

Type

Journal article

Journal

Circ Res

Publication Date

11/05/2001

Volume

88

Pages

911 - 917

Keywords

Adenoviridae, Adenovirus E1 Proteins, Adenovirus E1A Proteins, Adenovirus E4 Proteins, Animals, Carotid Arteries, Endothelium, Vascular, Gene Expression Regulation, Genetic Therapy, Genetic Vectors, Immunohistochemistry, Inflammation, Intercellular Adhesion Molecule-1, Male, Rabbits, Recombinant Fusion Proteins, Transgenes, Tunica Intima, Vascular Cell Adhesion Molecule-1, Vascular Diseases, Vasodilation, beta-Galactosidase