Mechanistic probing of gaseous signal transduction in microcirculation

Nitric oxide (NO) and carbon monoxide (CO) serve as activators of soluble guanylate cyclase (sGC) in vitro, and the latter serves as a microvascular relaxant for the liver, a major organ for heme oxygenase-dependent heme degradation and gas generation. Another important determinant of local sGC activities is superoxide anion, which scavenges NO and/or activates sGC directly. Altered bioavailability of the oxygen-derived species and its functional outcomes remain unknown, because information on amounts and distribution of these molecules has hardly been examined in vivo. Our recent studies provided evidence for such complex actions of multiple gases in vivo. Intravital visualization of NO in microcirculation revealed that two distinct sources, NO synthase-1 and -3, play a major role in the maintenance of NO in arteriolar and venular walls, respectively. Besides its vasorelaxing action in the hepatic microcirculation, CO could induce vasoconstriction in the resistant artery where NO is abundantly available; systemic blood pressure was elevated in transgenic mice overexpressing heme oxygenase-1 site-specifically in vascular smooth muscle cells. Such a relationship between the gases has also been demonstrated by mechanistic bioprobing of sGC function using novel monoclonal antibodies. This article aims to provide an overview of advances in visual assessment of the generation and reception of oxygen-derived gaseous mediators in vivo.