Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β<inf>3</inf> AR/iNOS pathway in rats exposed to chronic intermittent hypoxia

Hisashi Nagai, Ichiro Kuwahira, Daryl O. Schwenke, Hirotsugu Tsuchimochi, Akina Nara, Sayoko Ogura, Takashi Sonobe, Tadakatsu Inagaki, Yutaka Fujii, Rutsuko Yamaguchi, Lisa Wingenfeld, Keiji Umetani, Tatsuo Shimosawa, Kenichi Yoshida, Koichi Uemura, James T. Pearson, Mikiyasu Shirai

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Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β<inf>1</inf> - adrenergic receptors (AR) (brain) and peripheral β<inf>2</inf> AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β<inf>3</inf> AR. However, the relationship between IH and β<inf>3</inf> AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β<inf>3</inf> AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β<inf>3</inf> AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O<inf>2</inf>) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of proinflammatory pulmonary macrophages. In these macrophages, both β<inf>3</inf> AR and iNOS were upregulated and stimulation of the β<inf>3</inf> AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β<inf>3</inf> AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β<inf>3</inf> AR/iNOS signaling in chronic IH.

Original languageEnglish
Article numbere0131923
JournalPLoS One
Issue number7
Publication statusPublished - 2015 Jul 1
Externally publishedYes


ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nagai, H., Kuwahira, I., Schwenke, D. O., Tsuchimochi, H., Nara, A., Ogura, S., Sonobe, T., Inagaki, T., Fujii, Y., Yamaguchi, R., Wingenfeld, L., Umetani, K., Shimosawa, T., Yoshida, K., Uemura, K., Pearson, J. T., & Shirai, M. (2015). Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β<inf>3</inf> AR/iNOS pathway in rats exposed to chronic intermittent hypoxia. PLoS One, 10(7), [e0131923]. https://doi.org/10.1371/journal.pone.0131923