ADENOVIRUS-MEDIATED GENE-TRANSFER INTO NORMAL RABBIT ARTERIES RESULTSIN PROLONGED VASCULAR CELL ACTIVATION, INFLAMMATION, AND NEOINTIMAL HYPERPLASIA

Adenovirus vectors are capable of high efficiency in vivo arterial gen e transfer, and are currently in use as therapeutic agents in animal m odels of vascular disease, However, despite substantial data on the ab ility of viruses to cause vascular inflammation and proliferation, and the presence in current adenovirus vectors of viral open reading fram es that are translated in vivo, no study has examined the effect of ad enovirus vectors alone on the arterial phenotype, In a rabbit model of gene transfer into a normal artery, we examined potential vascular ce ll activation, inflammation, and neointimal proliferation resulting fr om exposure to replication-defective adenovirus, Exposure of normal ar teries to adenovirus vectors resulted in: (a) pronounced infiltration of T cells throughout the artery wall; (b) upregulation of intercellul ar adhesion molecule-1 and vascular cell adhesion molecule-1 in arteri al smooth muscle cells; (c) neointimal hyperplasia, These findings wer e present both 10 and 30 d after gene transfer, with no evidence of a decline in severity over time. Adenovirus vectors have pleiotropic eff ects on the arterial wall and cause significant pathology, Interpretat ion of experimental protocols that use adenovirus vectors to address e ither biological or therapeutic issues should take these observations into account. These observations should also prompt the design of more inert gene transfer vectors.