Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats

被引:198
作者
Janssens, S
Flaherty, D
Nong, ZX
Varenne, O
van Pelt, N
Haustermans, C
Zoldhelyi, P
Gerard, R
Collen, D
机构
[1] Catholic Univ Louvain, Hosp Gasthuisberg, Cardiac Unit, B-3000 Louvain, Belgium
[2] Catholic Univ Louvain, Hosp Gasthuisberg, Dept Radiotherapy, B-3000 Louvain, Belgium
[3] Flanders Interuniv Inst Biotechnol, Ctr Transgene Technol & Gene Therapy, Leuven, Belgium
关键词
nitric oxide; muscle; smooth; stenosis genes;
D O I
10.1161/01.CIR.97.13.1274
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Loss of endothelial NO production after arterial injury may contribute to restenosis, characterized by neointima formation and elastic recoil, Adenovirus-mediated transfer of the gene encoding NO synthase (NOS) in balloon-injured arteries may restore NO production and inhibit neointima formation. Methods and Results-After balloon injury, rat carotid arteries were transduced with 3x10(10) pfu/mL recombinant adenovirus carrying the human endothelial constitutive NOS cDNA (AdCMVceNOS, n=8) or no cDNA (AdRR5, n=8). ceNOS expression was confirmed by immunoblot analysis of vascular extracts and was localized by immunostaining in 30% of medial smooth muscle cells (SMCs) and in the adventitia of AdCMVceNOS-transduced arteries. Vascular cGMP levels were reduced from 3.9 pmol/g wet wt in uninjured arteries to 0.7 pmol cGMP/g after AdRR5 but were restored after ceNOS gene transfer (3.8 pmol cGMP/g wet wt, P<.05 versus AdRR5), Intima-to-media ratio 2 weeks after injury was significantly reduced (0.19+/-0.02 in AdCMVceNOS-infected versus 0.69+/-0.07 in AdRR5-infected arteries, P<.05). In vitro, BrdU incorporation of AdCMVceNOS-infected SMCs was reduced by 28% compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FAGS sorting showed a significantly lower BrdU labeling index in ceNOS-infected rats (29+/-6% versus 43+/-5% and 45+/-4% in control, injured, and AdRR5-infected rats, respectively, P<.05). Conclusions-AdCMVceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO productionand reduces neointima formation, at least in part because of an antiproliferative effect on medial SMCs. Adenovirus-mediated ceNOS gene transfer might reduce arterial restenosis after balloon angioplasty.
引用
收藏
页码:1274 / 1281
页数:8
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