Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice

Champion, Hunter C.; Bivalacqua, Trinity J.; Greenberg, Stanley S.; Giles, Thomas D.; Hyman, Albert L.; Kadowitz, Philip J.

doi:10.1073/pnas.182225899

Cited by 95Pulmonary Hypertension Research and TreatmentsNitric Oxide and Endothelin EffectsVirus-based gene therapy research

Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice

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Champion, Hunter C., Bivalacqua, Trinity J., Greenberg, Stanley S., Giles, Thomas D., Hyman, Albert L., Kadowitz, Philip J.·2002·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.182225899PMC PMC130619

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Abstract

It has been shown that mice deficient in the gene coding for endothelial nitric-oxide synthase (eNOS) have increased pulmonary arterial pressure and pulmonary vascular resistance. In the present study, the effect of transfer to the lung of an adenoviral vector encoding the eNOS gene (AdCMVeNOS) on pulmonary arterial pressure and pulmonary vascular resistance was investigated in eNOS-deficient mice. One day after intratracheal administration of AdCMVeNOS to eNOS(-/-) mice, there was an increase in eNOS protein, cGMP levels, and calcium-dependent conversion of l-arginine to l-citrulline in the lung. The increase in eNOS protein and activity in eNOS(-/-) mice was associated with a reduction in mean pulmonary arterial pressure and pulmonary vascular resistance when compared with values in eNOS-deficient mice treated with vehicle or a control adenoviral vector coding for beta-galactosidase, AdCMVbetagal. These data suggest that in vivo gene transfer of eNOS to the lung in eNOS(-/-) mice can increase eNOS staining, eNOS protein, calcium-dependent NOS activity, and cGMP levels and partially restore pulmonary arterial pressure and pulmonary vascular resistance to near levels measured in eNOS(+/+) mice. Thus, the major finding in this study is that in vivo gene transfer of eNOS to the lung in large part corrects a genetic deficiency resulting from eNOS deletion and may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders in which eNOS activity is reduced.

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The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation.
“The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation[28–34].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [31]

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Full Issue PDF
(2023) · Advances in Pulmonary Hypertension · doi:10.21693/1933-0898-22.1.i
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Gene Transfer of Endothelial Nitric Oxide Synthase to the Lung of the Mouse In Vivo
Champion, H. C., Bivalacqua, T. J., D’Souza, F. M., Ortiz, L. A., Jeter, J. R., Toyoda, K., Heistad, D. D., Hyman, A. L., & Kadowitz, P. J. (1999) · Circulation Research · doi:10.1161/01.res.84.12.1422 · Cited by 98 · see citing works
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Effect of adenovirus-mediated human endothelial nitric oxide synthase gene transfection on pulmonary hypertension rat model induced by high pulmonary blood flow
Wang, Y. (2010) · Journal of Shandong University
eNOS gene transfection on pulmonary artery hypertension and hypertension crisis in rabbits
Xian-shuo, L. (2010) · Journal of Shandong University
Effect of adenovirus-mediated gene transfer of nitric oxide synthase on vascular reactivity of rat isolated pulmonary arteries
Jiang, L.-F., Quarck, R. A., Janssens, S. P., Pokreisz, P., Demedts, M., & Delcroix, M. (2006) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-005-0028-3 · Cited by 6 · see citing works

Authors: Champion, H. C., Bivalacqua, T. J., Greenberg, S. S., Giles, T. D., Hyman, A. L., & Kadowitz, P. J.
Affiliations: Tulane University (US)
ORCID: Bivalacqua, Trinity J.
Giles, Thomas D.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2002-09-17
Volume: 99
Issue: 20
Pages: 13248-13253
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.182225899
PMC: PMC130619
OpenAlex: W1982535785
Cited by: 95
References: 27
Citations by year: 2025: 4 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 6 · 2012: 9
FWCI: 5.21
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Heart Association
National Institutes of Health
National Heart, Lung, and Blood Institute (HL-62000, R01HL062000)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords: endothelial nitric oxide synthase, eNOS deficiency, adenoviral gene transfer, pulmonary artery pressure, pulmonary vascular resistance, pulmonary hypertension, cyclic GMP, eNOS-deficient mice, nitric oxide
MeSH terms: Adenoviridae, Animals, Cyclic GMP, Hemodynamics, Hypertension, Pulmonary, Lung, Pressure, Time Factors, Transfection, Gene Transfer Techniques, Nitric Oxide Synthase, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III

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Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice

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