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PNAS 109 (4): 1293-1298

Copyright © 2012 by the National Academy of Sciences.


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

Takayuki Morikawaa,1, Mayumi Kajimuraa,b,1,2, Tomomi Nakamuraa,c, Takako Hishikia, Tsuyoshi Nakanishia,d, Yoshinori Yukutakea,b, Yoshiko Nagahatab, Mami Ishikawaa, Katsuji Hattoria, Toshiki Takenouchie, Takao Takahashie, Isao Ishiia, Kazuko Matsubaraa, Yasuaki Kabea,b, Shinichiro Uchiyamac, Eiichiro Nagataf, Moataz M. Gadallag,h, Solomon H. Snyderg,h,i,2, and Makoto Suematsua,b,2

aDepartment of Biochemistry, School of Medicine, Keio University, Tokyo 160-8582, Japan; bJapan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo 160-8582, Japan; cDepartment of Neurology, Tokyo Women's Medical University, Tokyo 162-8666, Japan; dMS Business Unit, Shimadzu Corporation, Kyoto 604-8511, Japan; eDepartment of Pediatrics, School of Medicine, Keio University, Tokyo 160-8582, Japan; fDepartment of Neurology, Tokai University School of Medicine, Kanagawa 259-1193, Japan; and gSolomon H. Snyder Department of Neuroscience, hDepartment of Pharmacology and Molecular Sciences, and iDepartment of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

Contributed by Solomon H. Snyder, December 11, 2011 (sent for review November 3, 2011)

Abstract: 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.

Key Words: gas biology • neurovascular unit • energy metabolism • gasotransmitter

Freely available online through the PNAS open access option.

Author contributions: M.K. and M.S. designed research; T.M., T. Nakamura, T.H., T. Nakanishi, Y.Y., Y.N., M.I., K.H., T. Takenouchi, T. Takahashi, K.M., Y.K., S.U., and M.M.G. performed research; I.I., E.N., M.M.G., and S.H.S. contributed new reagents/analytic tools; T.M., M.K., T. Nakamura, T.H., T. Nakanishi, Y.Y., Y.N., M.I., K.H., T. Takenouchi, T. Takahashi, K.M., Y.K., S.U., and M.M.G. analyzed data; and M.K., M.M.G., S.H.S., and M.S. wrote the paper.

1T.M. and M.K. contributed equally to this work.

The authors declare no conflict of interest.

This article contains supporting information online at

2To whom correspondence may be addressed. E-mail: gasbiology{at}, ssnyder{at}, or myk30{at}

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