Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse bra...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (4), p.1293-1298
Main Authors: Morikawa, Takayuki, Kajimura, Mayumi, Nakamura, Tomomi, Hishiki, Takako, Nakanishi, Tsuyoshi, Yukutake, Yoshinori, Nagahata, Yoshiko, Ishikawa, Mami, Hattori, Katsuji, Takenouchi, Toshiki, Takahashi, Takao, Ishii, Isao, Matsubara, Kazuko, Kabe, Yasuaki, Uchiyama, Shinichiro, Nagata, Eiichiro, Gadalla, Moataz M, Snyder, Solomon H, Suematsu, Makoto
Format: Article
Language:English
Subjects:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Adenosine triphosphatase
adenosine triphosphate
Adenosine Triphosphate - metabolism
adults
Analysis of Variance
Animals
Arterioles
ATP
Biological Sciences
Blood flow
Blood vessels
Blotting, Western
Brain
Brain hypoxia
Carbon
Carbon monoxide
Carbon Monoxide - metabolism
Cerebellum
Cerebral blood flow
cerebral cortex
Cerebrum - blood supply
Confocal microscopy
Cortex
Cystathionine beta -synthase
Cystathionine beta-Synthase - metabolism
Disposition
DNA Primers - genetics
Enzymes
Gene deletion
heme
Heme oxygenase (decyclizing)
Heme Oxygenase (Decyclizing) - genetics
Heme Oxygenase (Decyclizing) - metabolism
Hydrogen sulfide
Hydrogen Sulfide - metabolism
Hypoxia
Hypoxia - physiopathology
image analysis
Immunohistochemistry
Mass Spectrometry
Mass spectroscopy
Mice
Microcirculation - physiology
microscopy
Microscopy, Confocal
monitoring
Neuroimaging
Neurons
Oxygen
Physiological regulation
Regional Blood Flow - physiology
Rodents
Sensors
Signal transduction
Vasodilation
Vasodilation - physiology
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Summary:Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H2S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H2S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2–null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1119658109