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Hypoxic Regulation of the Cerebral Microcirculation Is Mediated by a Carbon Monoxide-Sensitive Hydrogen Sulfide Pathway

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Hypoxic Regulation of the Cerebral Microcirculation Is Mediated by a Carbon Monoxide-Sensitive Hydrogen Sulfide Pathway 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) Enhancement of cerebral blood flow by hypoxia is critical for brain athionine β-synthase (CBS) and cystathionine γ-lyase (CSE). In function, but signaling systems underlying its regulation have been peripheral blood vessels, CSE is localized to the endothelium, and unclear. We report a pathway mediating hypoxia-induced cerebral endothelial-derived relaxing factor activity in peripheral vessels is ∼ vasodilation in studies monitoring vascular disposition in cerebellar reduced by 75% in CSE-null mice (18). H2S exerts its physio- slices and in intact mouse brains using two-photon intravital laser logical actions by covalently modifying the sulfhydryl group of S scanning microscopy. In this cascade, hypoxia elicits cerebral vaso- cysteines in target proteins in a process termed -sulfhydration, which is analogous to S-nitrosylation by NO (22–25). The vaso- dilation via the coordinate actions of H2S formed by cystathionine β dilating actions of H2S are associated with sulfhydration of a spe- -synthase (CBS) and CO generated by heme oxygenase (HO)-2. fi Hypoxia diminishes CO generation by HO-2, an oxygen sensor. ci c cysteine in ATP-sensitive potassium (KATP) channels of blood The constitutive CO physiologically inhibits CBS, and hypoxia leads vessels, activating the channels and hyperpolarizing the vascular endothelial and smooth muscle cells (25). to increased levels of H2Sthatmediatethevasodilationofprecapil- The brain generates micromolar amounts of CO via HO-catalyzed lary arterioles. Mice with targeted deletion of HO-2 or CBS display reactions using O2 as a substrate, with HO-2 accounting for ∼80% of impaired vascular responses to hypoxia. Thus, in intact adult brain the total rodent brain HO activity (14, 26). A recent metabolomic – cerebral cortex of HO-2 null mice, imaging mass spectrometry study in murine liver using capillary electrophoresis-mass spec- reveals an impaired ability to maintain ATP levels on hypoxia. trometry (CE-MS) identified CBS as a CO sensor regulating bi- carbonate-dependent biliary choleresis (27). CBS is a hemethiolate NEUROSCIENCE gas biology | neurovascular unit | energy metabolism | gasotransmitter enzyme (28) that catalyzes multiple H2S-generating reactions (29, 30). The prosthetic heme of this enzyme (31–33) allows the reversible he cerebral circulation is maintained by autoregulation, which coordinate bonding of gaseous ligands, such as CO and NO (34). Tprevents marked alterations in response to changes in blood Interestingly, CO, but not NO, inhibits the activity of CBS in vitro pressure, whereas functional hyperemia links blood flow to neural (31, 32) and in vivo (27), making CBS a CO-specific sensor. activity (1). Blood flow regulation in the brain is modulated by O2 In the present study, we show that hypoxia-induced arteriolar (2), with increased cerebral blood flow in response to hypoxia critical vasodilation in brain slices and intact mice is mediated via for protecting the brain against diverse insults. Such regulation also a signaling system in which HO-2 is the O2 sensor. HO-2 uses O2 participates in functional hyperemia, as demonstrated by functional to generate CO, which tonically inhibits the ability of astrocytic MRI investigations indicating a transient decrease in O levels CBS, a CO-specific sensor (27, 31, 32), to generate vasodilatory 2 – – preceding activation of blood flow in response to neuronal firing (3). H2S (17 21). During hypoxia, inhibition of HO-2 mediated CO Alterations in cerebral blood flow in response to hypoxia and production occurs, with a corresponding release of the tonic neural activity are mediated via several neurotransmitter systems, inhibition of CBS, allowing it to generate H2S, which in turn with prominent involvement of the gaseous mediator nitric oxide elicits arteriolar vasodilation. (NO) (1, 2). In response to glutamate acting on NMDA receptors, neuronal NO synthase (nNOS) is activated by increases in in- Results tracellular calcium, with the generated NO stimulating soluble Neuronal and Endothelial Localization of HO-2 and Glial Localization of guanylyl cyclase, thereby increasing cGMP levels to dilate blood CBS. Because CBS accounts for the great bulk of H2S generation vessels (4). Functional hyperemia is decreased by ∼50% in rats in in the brain (35), and because its heme group provides a CO- response to inhibition of nNOS (5). Another gaseous mediator, CO (6–8), is also vasoactive. In some blood vessel systems (e.g., liver sinusoids), CO causes vasodilation, and inhibition of its bio- Author contributions: M.K. and M.S. designed research; T.M., T. Nakamura, T.H., synthetic enzyme HO-2 leads to vasoconstriction (9–13). However, T. Nakanishi, Y.Y., Y.N., M.I., K.H., T. Takenouchi, T. Takahashi, K.M., Y.K., S.U., and M.M.G. in the cerebral circulation, CO elicits vasoconstriction. Thus, HO performed research; I.I., E.N., M.M.G., and S.H.S. contributed new reagents/analytic tools; T.M., inhibitors cause cerebral vasodilation, an effect reversed by CO M.K., T. Nakamura, T.H., T. Nakanishi, Y.Y., Y.N., M.I., K.H., T. Takenouchi, T. Takahashi, K.M., (14). This action of CO cannot be readily explained by previously 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. identified CO receptors, such as soluble guanylyl cyclase (6–12, 15) The authors declare no conflict of interest. or potassium channels (13, 16), both of which mediate vasodilation. Freely available online through the PNAS open access option. The CO and NO systems interface; thus, the vasodilatory actions of 1T.M. and M.K. contributed equally to this work. HO inhibitors are partially reversed by inhibitors of NOS (14). 2To whom correspondence may be addressed. E-mail: [email protected], ssnyder@ A third gaseous mediator, H2S, is also vasoactive, eliciting va- jhmi.edu, or [email protected]. sodilation in both the peripheral and cerebral circulation (17–21). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. H2S can be physiologically generated by two enzymes, cyst- 1073/pnas.1119658109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1119658109 PNAS | January 24, 2012 | vol. 109 | no. 4 | 1293–1298 Downloaded by guest on October 2, 2021 sensing mechanism (27, 31, 32), we compared the localizations of with optimal spatial localizations for multiple gaseous molecular CBS in the brain with those of HO-2, the main CO-producing signals to control microvascular resistance (Fig. 1I). isozyme in the brain (14). Immunohistochemical analysis in the neonatal mouse cerebellum revealed expression of HO-2 in HO-2/CO Cerebral Vasoconstrictor Tone Is CBS-Dependent. It was neurons and endothelial cells (Fig. 1 A–D). In contrast, CBS was previously shown that HO inhibitors cause vasodilation in the pial expressed in Bergmann glia and astrocytes (Fig. 1 E–H). Con- microcirculation, suggesting that CO is responsible for a cerebral sistent with these observed CBS localizations, generation of H S vasoconstrictor tone (14). We confirm these findings, showing that 2 μ was abolished in primary astrocytic cultures from CBS-null mice the HO inhibitors zinc protoporphyrin-IX (ZnPP; 1 M) and μ (Fig. S1). Moreover, metabolomic analysis using CE-MS revealed chromium (III) mesoporphyrin-IX (CrMP; 1 M) dilated arte- ∼ that levels of cystathionine, another CBS product, were below the rioles in cerebellar slices by 50% at 60 min (Fig. 2). In contrast, limit of detection in primary astrocytic cultures from CBS-null copper protoporphyrin-IX, an analog that does not inhibit HO, C had no effect. Tricarbonyldichlororuthenium(II) dimer, [Ru mice (Fig. S1 ). In the cortex, CBS appears to be the main H2S- μ producing enzyme, given that expression of CSE, another H S- (CO)3Cl2]2, a CO-releasing molecule (CORM-2; 100 M) (37), 2 reversed the effect of ZnPP (Fig. 2C), confirming that CO is a tonic producing enzyme, is limited to vascular smooth muscle cells vasoconstrictor under basal conditions. surrounding large vessels in the subarachnoid space and in spe- This action of CO cannot be readily explained by previously cific neurons in striatum and hippocampus (Fig. S2). Pericytes, fi – – identi ed CO receptors, such as soluble guanylyl cyclase (6 12, 15) key effector contractile cells (36) surrounded by HO-2 containing or potassium channels (13, 16), both of which mediate vasodila- endothelia and CBS-containing astrocytic endfeet that physically tion. Based on previous studies indicating that physiological con- link neurons to the vasculature, compose a neurovascular unit centrations of CO can inhibit the ability of CBS to generate vasodilatory H2S(17–21, 26, 27, 38), we hypothesize that endog- enous CO serves as a tonic vasoconstrictor by inhibiting CBS, thus preventing the H2S-mediated vasodilatory response.
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