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  • Title: Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up₄A-Mediated Vascular Contraction.
    Author: Mahdi A, Jiao T, Tratsiakovich Y, Yang J, Östenson CG, Pernow J, Zhou Z.
    Journal: Int J Mol Sci; 2018 Dec 07; 19(12):. PubMed ID: 30544633.
    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.
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