Recombinant gene transfer of endothelial nitric oxide synthase augments coronary artery relaxations during hypoxia

David G. Cable, Vincent J. Pompili, Timothy O'Brien, Hartzell V Schaff

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background - Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results - Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 1010 pfu/mL) or eNOS (Ad.CMVeNOS; 1010 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F(2α) was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS (N(G)-monomethyl-L-arginine, 10-3 mol/L). Hypoxia-induced transient relaxation (95% N2-5% CO2) in Ad. CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls. Conclusions - Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

Original languageEnglish (US)
JournalCirculation
Volume100
Issue number19 SUPPL.
StatePublished - Nov 9 1999

Fingerprint

Nitric Oxide Synthase Type III
Coronary Vessels
Arteries
Adenoviridae
Genes
Nitric Oxide Synthase
Canidae
Coronary Vasospasm
Galactosidases
Adventitia
Prostaglandins F
Blood Vessels
Arginine
Albumins
Nitric Oxide
Immunohistochemistry
Phosphates
Monoclonal Antibodies
Hypoxia
Escherichia coli

Keywords

  • β-galactosidase
  • Arteries
  • Genes
  • Genetics
  • Hypoxia
  • Ischemia
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Recombinant gene transfer of endothelial nitric oxide synthase augments coronary artery relaxations during hypoxia. / Cable, David G.; Pompili, Vincent J.; O'Brien, Timothy; Schaff, Hartzell V.

In: Circulation, Vol. 100, No. 19 SUPPL., 09.11.1999.

Research output: Contribution to journalArticle

Cable, David G. ; Pompili, Vincent J. ; O'Brien, Timothy ; Schaff, Hartzell V. / Recombinant gene transfer of endothelial nitric oxide synthase augments coronary artery relaxations during hypoxia. In: Circulation. 1999 ; Vol. 100, No. 19 SUPPL.
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abstract = "Background - Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results - Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 1010 pfu/mL) or eNOS (Ad.CMVeNOS; 1010 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F(2α) was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS (N(G)-monomethyl-L-arginine, 10-3 mol/L). Hypoxia-induced transient relaxation (95{\%} N2-5{\%} CO2) in Ad. CMVeNOS arteries (45.2±8.8{\%}, n=6) was augmented compared with vehicle (26.3±6.0{\%}) or viral (27.2±7.1{\%}) controls. Conclusions - Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.",
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N2 - Background - Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results - Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 1010 pfu/mL) or eNOS (Ad.CMVeNOS; 1010 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F(2α) was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS (N(G)-monomethyl-L-arginine, 10-3 mol/L). Hypoxia-induced transient relaxation (95% N2-5% CO2) in Ad. CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls. Conclusions - Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

AB - Background - Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results - Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 1010 pfu/mL) or eNOS (Ad.CMVeNOS; 1010 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F(2α) was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS (N(G)-monomethyl-L-arginine, 10-3 mol/L). Hypoxia-induced transient relaxation (95% N2-5% CO2) in Ad. CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls. Conclusions - Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

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