Formation of Adenosine by Vascular Endothelium: a Homeostatic and Antithrombogenic Mechanism?

Summary

Under physiological conditions, concentrations of adenosine in arterial and venous blood are very similar, although the nucleoside is rapidly metabolized by blood cells and the vascular endothelium. In order to characterize the possible regulatory role of endothelial cells in the homeostasis of adenosine in the blood, studies concerning metabolism of adenosine and adenine nucleotides were carried out on cultured endothelial cells of various origin and on different vessel preparations.

Micro- and macrovascular endothelial cells are capable of both a continuous uptake and release of adenosine. Adenosine taken up can be incorporated into adenine nucleotides or catabolized, the relative proportions depending on its concentration. Adenosine released from the endothelium is preferentially derived from the breakdown of adenine nucleotides. All endothelial cells exhibit extraordinarily active ectonucleotidases (ATPase, ADPase, 5′-nucleotidase), whereby also extracellular nucleotides are rapidly degraded to adenosine. This adenosine can accumulate extracellularly, mainly in cultures of macrovascular endothelial cells owing to their slower rate of adenosine uptake and metabolism. Similar observations pertain to isolated perfused segments of rabbit caval veins with intact endothelium. In vessel preparations denuded of endothelium extracellular adenine nucleotide degradation yields far more inosine than adenosine.

The net production of adenosine from intra- and extracellular adenine nucleotides by the vascular endothelium in vivo must exceed endothelial uptake of the nucleoside. Otherwise, similar arterial and venous plasma levels could not be maintained, since adenosine is also taken up and metabolized by red blood cells. Based on these considerations one has to postulate a concentration gradient of adenosine to exist between the unstirred plasma layer at the endothelial surface and the central blood stream. We propose that adenosine of endothelial origin — intra- and extracellularly formed and highly concentrated at the luminal surface — may constitute an important antiaggregatory mechanism, which is part of the well-known antithrombogenicity of an intact endothelial lining.