Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension

Karen A. Fagan, Brian M Morrissey, Brian W. Fouty, Koichi Sato, Julie Wright Harral, Kenneth G. Morris, Marloes Hoedt-Miller, Shanda Vidmar, Ivan F. McMurtry, David M. Rodman

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Background: The importance of nitric oxide (NO) in hypoxic pulmonary hypertension has been demonstrated using nitric oxide synthase (NOS) knockout mice. In that model NO from endothelial NOS (eNOS) plays a central role in modulating pulmonary vascular tone and attenuating hypoxic pulmonary hypertension. However, the normal regulation of NOS expression in mice following hypoxia is uncertain. Because genetically engineered mice are often utilized in studies of NO, we conducted the present study to determine how hypoxia alters NOS expression in wild-type mice. Method: Mice were exposed to sea level, ambient conditions (5280 feet) or severe altitude (17,000 feet) for 6 weeks from birth, and hemodynamics and lung NOS expression were assessed. Results: Hypoxic mice developed severe pulmonary hypertension (right ventricular systolic pressure [RVsP] 60 mmHg) as compared with normoxic mice (27 mmHg). Using quantitative reverse-transcription PCR, it was found that expressions of eNOS and inducible NOS (iNOS) increased 1.5-fold and 3.5-fold, respectively, in the lung. In addition, the level of lung eNOS protein was increased, neuronal NOS (nNOS) protein was unchanged, and iNOS was below the limit of detection. Immunohistochemistry demonstrated no change in lung iNOS or nNOS staining in either central or peripheral areas, but suggested increased eNOS in the periphery following hypoxia. Conclusion: In mice, hypoxia is associated with increases in lung eNOS, possibly in iNOS, but not in nNOS; this suggests that the pattern of lung NOS expression following hypoxia must be considered in studies using genetically engineered mice.

Original languageEnglish (US)
Pages (from-to)306-313
Number of pages8
JournalRespiratory Research
Issue number5
StatePublished - 2001
Externally publishedYes


  • Hypoxia
  • Mice
  • Nitric oxide (NO)
  • Nitric oxide synthase (NOS)
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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