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Int. J. Mol. Sci. 2018, 19(12), 3942; https://doi.org/10.3390/ijms19123942 (registering DOI)

Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction

1
Unit of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm 17176, Sweden
2
Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm 17176, Sweden
Equal contribution.
*
Author to whom correspondence should be addressed.
Received: 19 November 2018 / Revised: 5 December 2018 / Accepted: 7 December 2018 / Published: 7 December 2018
PDF [602 KB, uploaded 7 December 2018]

Abstract

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.
Keywords: purinergic receptors; endothelial dysfunction; Up4A; vascular contraction; diabetes purinergic receptors; endothelial dysfunction; Up4A; vascular contraction; diabetes
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Mahdi, A.; Jiao, T.; Tratsiakovich, Y.; Yang, J.; Östenson, C.-G.; Pernow, J.; Zhou, Z. Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction. Int. J. Mol. Sci. 2018, 19, 3942.

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