Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up(4)A-Mediated Vascular Contraction

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up(4)A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up(4)A 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 Up(4)A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up(4)A-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, P2X(7)R, or P2Y(6)R significantly improved EDR in aortas. Vasoconstrictor response to Up(4)A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X(7)R but not P2Y(6)R. Depletion of major endothelial component nitric oxide enhanced Up(4)A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X(7)R, and P2Y(6)R 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.