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Nitric oxide signaling in hypoxia

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Abstract

Endothelial-derived nitric oxide (NO) is classically viewed as a regulator of vasomotor tone. NO plays an important role in regulating O2 delivery through paracrine control of vasomotor tone locally and cardiovascular and respiratory responses centrally. Very soon after the cloning and functional characterization of the endothelial nitric oxide synthase (eNOS), studies on the interaction between O2 and NO made the paradoxical finding that hypoxia led to decreases in eNOS expression and function. Why would decreases in O2 content in tissues elicit a loss of a potent endothelial-derived vasodilator? We now know that restricting our view of NO as a regulator of vasomotor tone or blood pressure limited deeper levels of mechanistic insight. Exciting new studies indicate that functional interactions between NO and O2 exhibit profound complexity and are relevant to diseases states, especially those associated with hypoxia in tissues. NOS isoforms catalytically require O2. Hypoxia regulates steady-state expression of the mRNA and protein abundance of the NOS enzymes. Animals genetically deficient in NOS isoforms have perturbations in their ability to adapt to changes in O2 supply or demand. Most interestingly, the intracellular pathways for O2 sensing that evolved to ensure an appropriate balance of O2 delivery and utilization intersect with NO signaling networks. Recent studies demonstrate that hypoxia-inducible factor (HIF) stabilization and transcriptional activity is achieved through two parallel pathways: (1) a decrease in O2-dependent prolyl hydroxylation of HIF and (2) S-nitrosylation of HIF pathway components. Recent findings support a role for S-nitrosothiols as hypoxia-mimetics in certain biological and/or disease settings, such as living at high altitude, exposure to small molecules that can bind NO, or anemia.

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Acknowledgments

J.J.H. is a recipient of an Ontario Graduate Scholarship. H.S.M. is a recipient of a CIHR Training Program in Regenerative Medicine Fellowship. P.A.M. holds the Keenan Chair in Medical Research at St. Michael’s Hospital and the University of Toronto and is supported by a grant from the Canadian Institute of Health research (CIHR MOP 79475).

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  1. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    J. J. David Ho & Philip A. Marsden

  2. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada

    H. S. Jeffrey Man & Philip A. Marsden

  3. Department of Medicine, Division of Nephrology, St. Michael’s Hospital, University of Toronto, Keenan Research Centre in the Li Ka Shing Knowledge Institute, 209 Victoria St., 5th floor, Rm 521, Toronto, ON, M5B 1C6, Canada

    J. J. David Ho, H. S. Jeffrey Man & Philip A. Marsden

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  1. J. J. David Ho
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  2. H. S. Jeffrey Man
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Correspondence to Philip A. Marsden.

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Ho, J.J.D., Man, H.S.J. & Marsden, P.A. Nitric oxide signaling in hypoxia. J Mol Med 90, 217–231 (2012). https://doi.org/10.1007/s00109-012-0880-5

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  • DOI: https://doi.org/10.1007/s00109-012-0880-5

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