Invited Review HIGHLIGHTED TOPIC Regulation of the Cerebral Circulation Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation

Leffler, Charles W., Helena Parfenova, Jonathan H. Jaggar, and Rui Wang. Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation. J Appl Physiol 100: 1065–1076, 2006; doi:10.1152/japplphysiol.00793.2005.— This review focuses on two gaseous cellular messenger molecules, CO and H2S, that are involved in cerebrovascular flow regulation. CO is a dilatory mediator in active hyperemia, autoregulation, hypoxic dilation, and counteracting vasoconstriction. It is produced from heme by a constitutively expressed enzyme [heme oxygenase (HO)-2] expressed highly in the brain and by an inducible enzyme (HO-1). CO production is regulated by controlling substrate availability, HO-2 catalytic activity, and HO-1 expression. CO dilates arterioles by binding to heme that is bound to large-conductance Ca -activated K channels. This binding elevates channel Ca sensitivity, that increases coupling of Ca sparks to large-conductance Ca -activated K channel openings and, thereby, hyperpolarizes the vascular smooth muscle. In addition to dilating blood vessels, CO can either inhibit or accentuate vascular cell proliferation and apoptosis, depending on conditions. H2S may also function as a cerebrovascular dilator. It is produced in vascular smooth muscle cells by hydrolysis of L-cysteine catalyzed by cystathione -lyase (CSE). H2S dilates arterioles at physiologically relevant concentrations via activation of ATP-sensitive K channels. In addition to dilating blood vessels, H2S promotes apoptosis of vascular smooth muscle cells and inhibits proliferationassociated vascular remodeling. Thus both CO and H2S modulate the function and the structure of circulatory system. Both the HO-CO and CSE-H2S systems have potential to interact with NO and prostanoids in the cerebral circulation. Much of the physiology and biochemistry of HO-CO and CSE-H2S in the cerebral circulation remains open for exploration.