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Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor

Abstract

Beyond serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide1 revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors (EDCFs) remains unclear. The supernatant obtained from mechanically stimulated human endothelial cells obtained from dermal vessels elicited a vasoconstrictive response in an isolated perfused rat kidney. A purinoceptor blocker had a greater effect than an endothelin receptor blocker in decreasing endothelially derived vasoconstriction in the isolated perfused rat kidney. The nucleotide uridine adenosine tetraphosphate (Up4A) was isolated from the supernatant of stimulated human endothelium and identified by mass spectrometry. Up4A is likely to exert vasoconstriction predominantly through P2X1 receptors, and probably also through P2Y2 and P2Y4 receptors. Plasma concentrations of Up4A that cause vasoconstriction are found in healthy subjects. Stimulation with adenosine 5′-triphosphate (ATP), uridine 5′-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress releases Up4A from endothelium, suggesting that Up4A contributes to vascular autoregulation. To our knowledge, Up4A is the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties. We conclude that Up4A is a novel potent nonpeptidic EDCF. Its vasoactive effects, plasma concentrations and its release upon endothelial stimulation strongly suggest that Up4A has a functional vasoregulatory role.

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Figure 1: Vasoconstrictive effects of supernatants from stimulated endothelial cells and isolation of Up4A.
Figure 2: Final purification step and identification of Up4A from the supernatants of stimulated endothelial cells.
Figure 3: Vascular effects and quantification of Up4A release after stimulation of endothelial cells and in human plasma.

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Acknowledgements

We thank M. Witt for accumulation of the FT-ICR mass spectra. We thank L. Lebeau for the gift of the internal standard. This study was supported by a grant of the Deutsche Forschungsgemeinschaft (Zi 315/15–1) and by a grant of the Hospal Research Funding (J. Jankowski).

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Correspondence to Joachim Jankowski.

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Jankowski, V., Tölle, M., Vanholder, R. et al. Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor. Nat Med 11, 223–227 (2005). https://doi.org/10.1038/nm1188

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