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

Stefan Janssens, Declan Flaherty, Zengxuan Nong, Olivier Varenne, Natasha Van Pelt, Carine Haustermans, Pierre Zoldhelyi, Robert Gerard, Desire Collen, Elizabeth Nabel

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

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 3 x 1010 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 AdCMV ceNoS-infected SMCs was reduced by 28% compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FACS 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: AdCMV ceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO production and 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.

Original languageEnglish (US)
Pages (from-to)1274-1281
Number of pages8
JournalCirculation
Volume97
Issue number13
StatePublished - Apr 7 1998

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Neointima
Nitric Oxide Synthase Type III
Vascular Smooth Muscle
Smooth Muscle Myocytes
Arteries
Cell Proliferation
Blood Vessels
Wounds and Injuries
Bromodeoxyuridine
Carotid Arteries
Adenoviridae
Nitric Oxide Synthase
Genes
Complementary DNA
Carotid Artery Injuries
Human Adenoviruses
Adventitia
Balloon Angioplasty

Keywords

  • Genes
  • Muscle
  • Nitric oxide
  • Smooth
  • Stenosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Janssens, S., Flaherty, D., Nong, Z., Varenne, O., Van Pelt, N., Haustermans, C., ... Nabel, E. (1998). Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats. Circulation, 97(13), 1274-1281.

Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats. / Janssens, Stefan; Flaherty, Declan; Nong, Zengxuan; Varenne, Olivier; Van Pelt, Natasha; Haustermans, Carine; Zoldhelyi, Pierre; Gerard, Robert; Collen, Desire; Nabel, Elizabeth.

In: Circulation, Vol. 97, No. 13, 07.04.1998, p. 1274-1281.

Research output: Contribution to journalArticle

Janssens, S, Flaherty, D, Nong, Z, Varenne, O, Van Pelt, N, Haustermans, C, Zoldhelyi, P, Gerard, R, Collen, D & Nabel, E 1998, 'Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats', Circulation, vol. 97, no. 13, pp. 1274-1281.
Janssens, Stefan ; Flaherty, Declan ; Nong, Zengxuan ; Varenne, Olivier ; Van Pelt, Natasha ; Haustermans, Carine ; Zoldhelyi, Pierre ; Gerard, Robert ; Collen, Desire ; Nabel, Elizabeth. / Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats. In: Circulation. 1998 ; Vol. 97, No. 13. pp. 1274-1281.
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abstract = "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 3 x 1010 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 AdCMV ceNoS-infected SMCs was reduced by 28{\%} compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FACS 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: AdCMV ceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO production and 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.",
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AU - Janssens, Stefan

AU - Flaherty, Declan

AU - Nong, Zengxuan

AU - Varenne, Olivier

AU - Van Pelt, Natasha

AU - Haustermans, Carine

AU - Zoldhelyi, Pierre

AU - Gerard, Robert

AU - Collen, Desire

AU - Nabel, Elizabeth

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N2 - 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 3 x 1010 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 AdCMV ceNoS-infected SMCs was reduced by 28% compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FACS 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: AdCMV ceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO production and 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.

AB - 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 3 x 1010 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 AdCMV ceNoS-infected SMCs was reduced by 28% compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FACS 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: AdCMV ceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO production and 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.

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