Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation

Abstract

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 Ca²⁺-activated K⁺channels. This binding elevates channel Ca²⁺sensitivity, that increases coupling of Ca²⁺sparks to large-conductance Ca²⁺-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 γ-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 proliferation-associated 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.