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

Jiangning Yang,Yahor Tratsiakovich,Ali Mahdi,Tong Jiao,Claes-Göran Östenson,John Pernow,Zhichao Zhou

doi:10.3390/ijms19123942

Jiangning Yang, Yahor Tratsiakovich

Open Access

https://doi.org/10.3390/ijms19123942

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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.

Highlights

Type 2 diabetes (T2D) is an important risk factor for the development of cardiovascular disease including atherosclerosis and ischemic heart disease
The underlying cause of endothelial dysfunction is multifactorial and complex, but some of the key mechanisms include imbalance between endothelium-derived vasodilators such as nitric oxide (NO) and adenosine triphosphate (ATP), and vasoconstrictors such as endothelin, reactive oxygen species, and ATP, as well as receptor-mediated signaling activated by certain endothelium-derived factors, e.g., ATP-activated purinergic signaling [3,4]
We evaluated endothelial function based on acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR) and used Up4A as pharmacological stimulator for purinergic activation in both conduit and resistance arteries from Goto Kakizaki (GK) rats

Summary

Introduction

Type 2 diabetes (T2D) is an important risk factor for the development of cardiovascular disease including atherosclerosis and ischemic heart disease. The underlying cause of endothelial dysfunction is multifactorial and complex, but some of the key mechanisms include imbalance between endothelium-derived vasodilators such as nitric oxide (NO) and adenosine triphosphate (ATP), and vasoconstrictors such as endothelin, reactive oxygen species, and ATP, as well as receptor-mediated signaling activated by certain endothelium-derived factors, e.g., ATP-activated purinergic signaling [3,4]. Activation of purinergic receptors (PRs) by various extracellular nucleotides and nucleosides play a pivotal role in the control of vascular function. Due to a lack of specific antagonists for the most of PRs, the precise role of PRs in control of vascular function, in particular the contribution of those PRs to the development of endothelial dysfunction in T2D, remains to be determined

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