Gene transfer into rabbit arteries with adeno-associated virus and adenovirus vectors.
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 x 10(8) to 4 x 10(9) TU/ml) for their usefulness to transduce rabbit arteries in vivo in comparison with adenoviruses (Adv; 1 x 10(9) to 1 x 10(10) pfu/ml). 100 microl 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.
Gruchała
Marcin
M
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
Bhardwaj
Shalini
S
Pajusola
Katri
K
Roy
Himadri
H
Rissanen
Tuomas T
TT
Kokina
Ilze
I
Kholová
Ivana
I
Markkanen
Johanna E
JE
Rutanen
Juha
J
Heikura
Tommi
T
Alitalo
Kari
K
Büeler
Hansruedi
H
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000009:adverse effects; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011817:Rabbits; D042810:Receptor, TIE-1 / Q000235:genetics; D014161:Transduction, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D019010:Vascular Cell Adhesion Molecule-1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D042810:Receptor, TIE-1