Adenovirus-mediated delivery of the Gax transcription factor to rat carotid arteries inhibits smooth muscle proliferation and induces apoptosis.
Adenovirus-mediated gene delivery in animal models of vascular injury has provided insights into the mechanisms underlying vessel wall pathologies. We have previously demonstrated that overexpression of the Gax transcription factor inhibits neointimal formation in rat and rabbit models of arterial injury. Here, we evaluate potential mechanisms for the reduction in stenotic lesion size due to Gax overexpression. At 3, 7 and 14 days after injury the Ad-Gax-infected arteries displayed a marked decrease in medial vascular smooth muscle cell number (3 days, 54% reduction P < 0.01; 7 days, 41% reduction P < 0.003; 14 days, 49% reduction P < 0.02). At 3 days after injury, PCNA expression was attenuated in the Ad-Gax-treated vessels compared with control vessels (65% reduction P < 0.02), indicating a reduction in cellular proliferation. At 7 days and 14 days after injury Ad-Gax-infected arteries exhibited elevated number of TUNEL-positive medial VSMCs compared with control-treated arteries (7 days, 9.2-fold increase P < 0.03; 14 days, 17.2-fold increase P < 0.03), indicating an induction of apoptotic cell death. These data suggest that deregulated Gax expression induces first cell cycle arrest and then apoptosis in the vascular smooth muscle cells that contribute to the neointimal layer. Therefore, the efficacy of this therapeutic strategy appears to result from the ability of the Gax transcriptional regulator to modulate multiple cellular responses.
Perlman
H
H
Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Luo
Z
Z
Krasinski
K
K
Le Roux
A
A
Mahfoudi
A
A
Smith
R C
RC
Branellec
D
D
Walsh
K
K
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020212:Carotid Artery Injuries / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D008297:Male; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics*
D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors