Blood vessels of the vertebrate circulatory system are known to react to local changes in oxygen tension and thus the vasculature is finely adjusted to match perfusion to the physiological needs of each region of the body. In arteries of the systemic circulation, which provide oxygen-rich blood to the body, reduced levels of oxygen in tissues (hypoxia) trigger a dilatation of the vessels to improve delivery of blood and therefore oxygen. For many years it has been known (and become a paradigm) that in mammals the vessels that deliver oxygen-depleted blood to the lungs, the pulmonary arteries, react to pulmonary hypoxia via the exact opposite reaction, they constrict and thus reduce blood flow to hypoxic areas. This hypoxic vasoconstriction is a major mechanism for ensuring that blood is shunted to areas of the lungs that are highly ventilated (i.e. high in oxygen); the result is more efficient or complete gas exchange, which is of course the primary function of the lungs. The mechanisms by which the vascular cells sense and react to oxygen are not fully understood, but it is known that several cell types are involved. Ken Olson and colleagues at the Indiana University School of Medicine were investigating the role of hydrogen sulfide (H2S – which smells of rotten eggs) signaling in the control of vasculature dilatation state in sea lion lungs when they found something new – hypoxic vasodilatation in pulmonary arteries. Further, they provide strong evidence that H2S is the primary signal that the vessels respond to, and not reduced oxygen per se.
The team used a variety of methods to investigate the role of hypoxia and H2S in controlling the dilatation state of pulmonary arteries from both cows and sea lions. First, they exposed chunks of isolated pulmonary resistance arteries (those that are critical for controlling blood flow changes in the lungs) to hypoxia and H2S (100–300 μmol l−1) and measured their response to the signals using vessel myography. They also checked for expression of the major enzymes known to be important in the production of H2S using immunohistochemistry and western blotting. Finally, using probes specific to oxygen and H2S, they measured the ability of the tissues to produce H2S and investigated the relationship between levels of oxygen and levels of H2S in homogenates prepared from lung tissues.
Their results were surprising. Cow lungs responded to hypoxia and H2S in a similar fashion and as expected by constricting. However, sea lion lungs responded to both signals by dilating. The team found that the enzymes required to produce H2S were present and H2S was produced in the lung tissue of both species. Further, they found that levels of H2S and oxygen were inversely related, and H2S levels began to rise at physiologically relevant levels of hypoxia that elicit a reaction from the lung arteries. Thus, it appears that cows and sea lions may both use H2S to signal low oxygen conditions in the pulmonary arteries, but they respond to the same signal with opposite responses.
The discovery of hypoxic vasodilatation in the pulmonary arteries of sea lions is surprising and significant. The reason for this difference is likely adaptive and related to the diving physiology of marine mammals. However, perhaps the more interesting conclusion is that H2S may act as an oxygen sensor in these tissues. The model that Olson and colleagues propose for H2S as an oxygen sensor requires continuous cytoplasmic production of H2S. Under normal oxygen levels the H2S is simultaneously removed by mitochondrial oxidation; however, when tissues become hypoxic and oxygen scarce, H2S oxidation is reduced, leading to a rise in H2S levels.
Given that the enzymes required to produce H2S are widespread in animal tissues, it is likely that this simple, elegant, and powerful mechanism may underlie oxygen sensing and signaling in many physiological contexts where oxygen sensors have been postulated to exist, but are yet to be identified.
