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Oxygen and Two Friends

The cerebral vasculature responds to reduced oxygen through a pathway involving carbon monoxide and hydrogen sulfide. The brain needs to regulate blood flow in response to neural activity and changes in blood pressure. Various gases regulate vascular tone in response to hypoxia, including nitric oxide (NO, vasodilation), carbon monoxide (CO, vasoconstriction or vasodilation, depending on the vessel), and hydrogen sulfide (H2S, vasodilation). Morikawa et al. describe a cerebral vascular regulatory loop involving CO and H2S that contributes to the vasodilatory response of some blood vessels in response to hypoxia. H2S is synthesized by cystathionine β-lyase (CBS), and CO is produced by heme oxygenase-2 (HO-2), and these two enzymes were located in glia and astrocytes (CBS) and in neurons and endothelial cells (HO-2) in neonatal mouse cerebellum. The authors propose that this provides an optimal location of these enzymes in a neurovascular unit that includes contractile cells, surrounded by the HO-2–containing endothelia and the CBS-containing astrocytic endfeet. In neonatal cerebellar slices, pharmacological inhibition of HO-2 promoted vasodilation in slices from wild-type mice but not in slices from CBS-knockout mice, indicating that CO acted as a tonic vasoconstrictor and suggesting that H2S might mediate the vasodilation that occurs upon the reduction in CO. Knockout of either HO-2 or CBS impaired the hypoxia-induced vasodilatory response of neonatal cerebellar slices. CO concentration decreased and H2S concentration increased in slices from wild-type mice in response to hypoxic conditions, and these responses were lost in slices from HO-2–deficient mice. Using two-photon imaging of the cerebral cortex, the authors examined changes in blood flow in adult mice. A reduction in inhaled oxygen resulted in dilation of arterioles that penetrate into the brain and precapillary arterioles. The precapillary dilatory response was compromised in HO-2–knockout mice and was abolished in the CSE-knockout mice. Thus, the authors propose that, under conditions of normoxia, vascular tone is maintained by CO produced by HO-2 (an oxygen-dependent enzyme) and inhibits CBS activity. When oxygen becomes limiting, HO-2 is inhibited, CO drops, and CBS becomes active, producing H2S, which triggers vasodilation. T. Morikawa, M. Kajimura, T. Nakamura, T. Hishiki, T. Nakanishi, Y. Yukutake, Y. Nagahata, M. Ishikawa, K. Hattori, T. Takenouchi, T. Takahashi, I. Ishii, K. Matsubara, Y. Kabe, S. Uchiyama, E. Nagata, M. M. Gadalla, S. H. Snyder, M. Suematsu, Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. Proc. Natl. Acad. Sci. U.S.A. 109, 1293–1298 (2012). [Abstract] [Full Text]