AUTHOR=Mahdi Ali , Tratsiakovich Yahor , Tengbom John , Jiao Tong , Garib Lara , Alvarsson Michael , Yang Jiangning , Pernow John , Zhou Zhichao 

TITLE=Erythrocytes Induce Endothelial Injury in Type 2 Diabetes Through Alteration of Vascular Purinergic Signaling

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.603226

DOI=10.3389/fphar.2020.603226

ISSN=1663-9812

ABSTRACT=<p>It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h <italic>ex vivo</italic> co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after <italic>in vivo</italic> transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects <italic>ex vivo,</italic> and in aortas of healthy rats after transfusion with GK RBCs <italic>in vivo</italic>. The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X<sub>7</sub>R but not P2Y<sub>6</sub>R antagonism. Transfusion with GK RBCs <italic>in vivo</italic> impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X<sub>7</sub>R but not P2Y<sub>6</sub>R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X<sub>7</sub>R but not P2Y<sub>6</sub>R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D.</p>