Mechanisms of ATP release and signalling in the blood vessel wall

Abstract

The nucleotide adenosine 5'-triphosphate (ATP) has classically been considered the cell's primary energy currency. Importantly, a novel role for ATP as an extracellular autocrine and/or paracrine signalling molecule has evolved over the past century and extensive work has been conducted to characterize the ATP-sensitive purinergic receptors expressed on almost all cell types in the body. Extracellular ATP elicits potent effects on vascular cells to regulate blood vessel tone but can also be involved in vascular pathologies such as atherosclerosis. While the effects of purinergic signalling in the vasculature have been well documented, the mechanism(s) mediating the regulated release of ATP from cells in the blood vessel wall and circulation are now a key target of investigation. The aim of this review is to examine the current proposed mechanisms of ATP release from vascular cells, with a special emphasis on the transporters and channels involved in ATP release from vascular smooth muscle cells, endothelial cells, circulating red blood cells, and perivascular sympathetic nerves, including vesicular exocytosis, plasma membrane F(1)/F(0)-ATP synthase, ATP-binding cassette (ABC) transporters, connexin hemichannels, and pannexin channels.

Figure 1

Mechanisms of ATP release from cells of the blood vessel wall. Representative illustration of the currently proposed mechanisms of ATP release from endothelial cells, vascular smooth muscle cells, perivascular sympathetic nerves, and circulating erythrocytes in the vascular system. Cytosolic ATP available for release from these cells is generated by glycolysis in the cytosol and oxidative phospohorylation in the mitochondria. In sympathetic nerves, ATP release has been shown to occur via vesicular exocytosis. Vascular smooth muscle cells have been suggested to release ATP through membrane transporters and channels, including connexin hemichannels and pannexin channels, as well as potentially by ABC transporters. Vascular endothelial cells have been proposed to release ATP via vesicular exocytosis, ABC-transporters, connexin hemichannels, pannexin channels, and by direct synthesis at the extracellular plasma membrane by a cell surface F₁/F₀-ATP synthase. Circulating erythrocytes have been suggested to release ATP through ABC transporters and via pannexin channels.