Vascular biology

Nitric oxide caught in traffic

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Nitric oxide is a vital signalling molecule that controls blood flow and pressure. Unexpectedly, a redox switch in the protein haemoglobin α within endothelial cells regulates this molecule's diffusion in blood vessels. See Letter p.473

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Nitric oxide is a vasodilator. It is produced in endothelial cells, which line blood vessels, and mediates signalling cascades in adjoining smooth-muscle cells to affect the regulation of blood pressure, blood flow and oxygen delivery. Nitric oxide is proposed to control these crucial physiological processes through simple unregulated diffusion from its site of production to its target sites. But on page 473 of this issue, Straub and colleagues provide evidence1 that the oxidation state of the protein haemoglobin α, which is expressed at the junction between endothelial and muscle cells, regulates nitric oxide diffusion and signallingFootnote 1.

Haemoglobin is best known for mediating oxygen delivery by erythrocytes (red blood cells). Nonetheless, low concentrations of this protein are expressed in other cells, such as human lung epithelial cells2. In addition, over the past 15 years several primordial globins— including neuroglobin and cytoglobin — have been discovered that are expressed in various non-erythrocytic organs such as the brain, retina, endocrine organs and vascular smooth muscle. Functions that are being explored for these proteins include mediating electron-transfer reactions (such as the reduction of the enzyme cytochrome c and nitrite (NO2) reduction) and nitric oxide (NO) scavenging reactions3,4. For instance, flavohaemoglobins and myoglobin have been proposed4,5 to limit NO signalling by converting it to nitrate (NO3) in a dioxygenation reaction. A role for haemoglobin in NO-scavenging reactions is appealing on theoretical grounds because these reactions are fast and can occur at the low globin concentrations found in cells.

The unique diffusion properties of NO (it forms a spherical concentration gradient around its source) create challenges for directional and compartmental signalling by this molecule. To reach its signalling target, NO must escape reactions that convert it to inert species.

Several solutions have evolved. These include spatial localization and control of NO production within cell-membrane structures called caveoli, and within hot spots of metabolic enzymes, where NO is coupled to its target. Alternatively, Straub et al. propose that the thick walls of the internal elastic lamina (the outermost elastic tissue of blood vessels that separates endothelium and smooth- muscle cells) create physical distance between the source of NO production (the enzyme endothelial NO synthase) and the NO target, the smooth-muscle soluble guanylyl cyclase enzyme.

At regular points between the endothelium and smooth muscle, known as myoendothelial junctions (MEJs), the cells project through the internal elastic lamina and 'kiss' each other, increasing the NO concentration at these corridors. These points of cell–cell contact contain gap-junction channels that allow electrical coupling and intercellular diffusion of vasodilatory factors, such as eicosanoids, potassium ions and hydrogen peroxide, and small solutes that can dynamically regulate blood-vessel diameter6. Straub et al. propose that these junctions also create corridors within the internal elastic lamina for NO diffusion.

The authors find that haemoglobin α is concentrated at the MEJs. Here, this protein serves to block NO diffusion to smooth muscle, specifically through the extremely fast and irreversible dioxygenation reaction of NO with ferrous (Fe2+) oxyhaemoglobin to form nitrate and methaemoglobin, in which the iron in the haem group of haemoglobin is in the ferric (Fe3+) state7,8.

The team also reports that the enzyme cytochrome b5 reductase 3 — also called methaemoglobin reductase — forms a complex with cellular haemoglobin α and regulates NO diffusion by reducing the Fe3+-haem to the oxygen-binding Fe2+-haem. This provides an enzymatic mechanism to control NO diffusion (Fig. 1), because only the Fe2+-haem can scavenge NO. By contrast, the Fe3+-haem does not bind NO tightly and so allows its diffusion through the MEJ to the smooth muscle, where it activates soluble guanylyl cyclase and mediates the downstream signalling cascade.

Figure 1: Regulation of nitric oxide (NO) diffusion by cytochrome b5 reductase 3.

Endothelial cells of blood vessels connect to their neighbouring muscle cells through myoendothelial junctions (MEJs), which span internal elastic lamina. a, Straub et al.1 show that when cytochrome b5 reductase 3 is inactive, the abundant haemoglobin α at the MEJs is in the ferric (Fe3+) methaemoglobin state, which does not bind tightly to the vasodilator NO. Consequently, NO passes to muscle cells where it mediates signalling cascades that result in vasodilation through activation of soluble guanylyl cyclase. b, Active cytochrome b5 reductase 3 forms a complex with methaemoglobin α, reducing it to the Fe2+ state. The latter blocks NO diffusion to smooth muscle, through a dioxygenation reaction that results in the formation of nitrate (NO3).

Another outcome of NO interaction with methaemoglobin is reductive nitrosylation, which can form the signalling molecules nitrite or S-nitrosothiols9. Both nitrite and S-nitrosothiols can regulate NO signalling independently of soluble guanylyl cyclase and by post-translational modification of target proteins. However, the reductive nitrosylation reaction is some 200 times slower than the scavenging reactions9. Nonetheless, the Fe3+-methaemoglobin allows NO to diffuse through the MEJ or to react and form the freely diffusible nitrite and S-nitrosothiols.

Straub and colleagues' work complements other studies3,10,11 that were conducted under conditions of hypoxia (oxygen shortage) and which found that deoxygenated globins can function as nitrite reductase enzymes that react with nitrite to generate NO. For instance, when oxygen levels are low in smooth-muscle cells, myoglobin can reduce nitrite to NO, contributing to vasodilation11. In this reaction, the Fe2+-deoxymyoglobin transfers an electron to nitrite to form NO and metmyoglobin. It seems, therefore, that globins can limit NO signalling when reduced or oxygenated and enhance NO signalling when oxidized or deoxygenated (Fig. 1).

This paper highlights a novel function of the MEJ as an NO diffusion corridor. The expression and localization of haemoglobin α chains and cytochrome b5 reductase 3 at the MEJ constitute a specific checkpoint or traffic light for redox-regulated NO diffusion at these corridors. Future work must clarify the post-translational modifications of cytochrome b5 reductase 3 that control its activity, and which would ideally couple activation of NO synthase to NO diffusion and MEJ 'gate opening'. Moreover, haemoglobin functions beyond NO scavenging must be explored, not least because of the widespread expression of cellular haemoglobins in plants, which do not possess NO synthase enzymes.


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    *This article and the paper under discussion1 were published online on 31 October 2012.


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Correspondence to Mark T. Gladwin.

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Gladwin, M., Kim-Shapiro, D. Nitric oxide caught in traffic. Nature 491, 344–345 (2012) doi:10.1038/nature11640

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