Adenoviral delivery of a constitutively active retinoblastoma mutant inhibits neointima formation in a human explant model for vein graft disease.
Intimal hyperplasia resulting from vascular injury remains a major obstacle in the long-term success of coronary artery bypass grafts. Inhibition of smooth muscle cell (SMC) proliferation using adenoviral gene transfer of cell cycle inhibitors resulted in reduced neointima formation in various animal models. However, little is known about the effect on human SMCs and neointima formation. Here we report the effects of infection with an adenoviral vector encoding a constitutively active form of the retinoblastoma gene (Ad. delta Rb) on proliferation of human saphenous vein SMCs (HSVSMCs) and neointima formation in organ cultures of human saphenous vein. Proliferation of SMCs was inhibited dose-dependently after infection with Ad. delta Rb. A near-total inhibition was found at an Ad. delta Rb concentration of 10(8) pfu/ml. Organ cultures of human saphenous vein segments were used to evaluate the effect of Ad. delta Rb infection on neointima formation and vein graft disease. Segments cultured for 4 weeks develop a neointima that is morphologically highly similar to early initimal lesions found in pathological vein grafts in vivo. Infection of saphenous vein segments with 2 x 10(9) pfu/ml Ad. delta Rb resulted in a 59% reduction of neointimal area when compared to uninfected counterparts, whereas infection with control adenovirus, Ad.LacZ, had no significant effect. The results of this study show that Ad. delta Rb gene transfer might be an efficient approach to prevent neointima formation in human saphenous vein grafts.
Lamfers
Martine L
ML
Gaubius Laboratory, TNO-PG, P.O. Box 2215, 2301 CE Leiden, The Netherlands.
Aalders
Marjanka C
MC
Grimbergen
Jos M
JM
de Vries
Margreet R
MR
Kockx
Mark M
MM
van Hinsbergh
Victor W
VW
Quax
Paul H
PH
D000256:Adenoviridae / Q000235:genetics*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D006083:Graft Occlusion, Vascular / Q000235:genetics / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019572:Retinal Neoplasms / Q000235:genetics*; D012175:Retinoblastoma / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein / Q000166:cytology / Q000254:growth & development; D001616:beta-Galactosidase / Q000378:metabolism
D012333:RNA, Messenger; D001616:beta-Galactosidase