THE JOURNAL OF GENE MEDICINE RESEARCH ARTICLE J Gene Med 2004; 6: 545–554. Published online 20 February 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jgm.535 Gene transfer into rabbit arteries with adeno-associated virus and adenovirus vectors Marcin Gruchala 1,3 Shalini Bhardwaj 1 Katri Pajusola 2 Himadri Roy 1 Tuomas T. Rissanen 1 Ilze Kokina 1 Ivana Kholov´ a 1 Johanna E. Markkanen 1 Juha Rutanen 1 Tommi Heikura 1 Kari Alitalo 6 Hansruedi B¨ ueler 2 Seppo Yl¨ a-Herttuala 1,4,5 * 1 Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland 2 Institute of Molecular Biology, University of Zurich, Switzerland 3 First Department of Cardiology, Medical University of Gda´ nsk, Poland 4 Department of Medicine University of Kuopio, Finland 5 Gene Therapy Unit, Kuopio University Hospital, Finland 6 Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, Finland *Correspondence to: Seppo Yl¨ a-Herttuala, Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: Seppo.Ylaherttuala@uku.fi Received: 9 September 2003 Revised: 4 December 2003 Accepted: 8 December 2003 Abstract Background Gene transfer offers considerable potential for altering vessel wall physiology and intervention in vascular disease. Therefore, there is great interest in developing optimal strategies and vectors for efficient, targeted gene delivery into a vessel wall. Methods We studied adeno-associated viruses (AAV; 9 × 10 8 to 4 × 10 9 TU/ml) for their usefulness to transduce rabbit arteries in vivo in comparison with adenoviruses (Adv; 1 × 10 9 to 1 × 10 10 pfu/ml). 100 μl of viruses or placebo solution were injected intraluminally into transiently isolated carotid segments. Results In normal arteries AAV transduced mainly medial smooth muscle cells (SMC) while Adv transduced exclusively endothelial cells (EC). Mechanical injury to EC layer and internal elastic lamina enabled Adv to penetrate and transduce medial SMC. Transgene expression in EC after the AAV-mediated gene transfer was very low. The use of the EC-specific Tie-1 promoter did not lead to specific transgene expression in EC. Transgene expression in SMC persisted for at least 100 days after the AAV treatment whereas the Adv-mediated effect diminished in 14 days. AAV caused only a modest increase in EC VCAM- 1 expression and proliferation rate of vascular cells as compared with the mock-treated arteries while Adv caused an extensive inflammatory cell infiltration, VCAM-1 expression, vascular cell proliferation and morphological damages. Conclusions Significant differences were observed between the AAV and the Adv vectors in their patterns of arterial transduction and consequent inflammatory responses. These distinct properties may be utilized for different applications in vascular biology research and gene therapy for cardiovascular diseases. Copyright  2004 John Wiley & Sons, Ltd. Keywords AAV; adenovirus; gene transfer; gene therapy; cardiovascular; artery; vector Introduction Local gene transfer into the arterial wall is potentially useful for many appli- cations in vascular biology, elucidation of the pathogenesis of atherosclerosis, and gene therapy of cardiovascular diseases [1]. Successful gene trans- fer to blood vessels has been accomplished by several vectors which each have specific advantages and limitations [1–3]. Currently, viral vectors are the vehicles of choice because of their high gene transfer efficiency [1]. Copyright  2004 John Wiley & Sons, Ltd.