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 brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H(2)S 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 H(2)S 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.
Department of Biochemistry, School of Medicine,  Keio University, Tokyo 160-8582,  Japan.
Takayuki
T
Morikawa
Mayumi
M
Kajimura
Tomomi
T
Nakamura
Takako
T
Hishiki
Tsuyoshi
T
Nakanishi
Yoshinori
Y
Yukutake
Yoshiko
Y
Nagahata
Mami
M
Ishikawa
Katsuji
K
Hattori
Toshiki
T
Takenouchi
Takao
T
Takahashi
Isao
I
Ishii
Kazuko
K
Matsubara
Yasuaki
Y
Kabe
Shinichiro
S
Uchiyama
Eiichiro
E
Nagata
Moataz M
MM
Gadalla
Solomon H
SH
Snyder
Makoto
M
Suematsu
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism*; D054022:Cerebrum / Q000098:blood supply*; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D051379:Mice; D008833:Microcirculation / Q000502:physiology*; D018613:Microscopy, Confocal; D012039:Regional Blood Flow / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D017931:DNA Primers; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002248:Carbon Monoxide; D000255:Adenosine Triphosphate; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide