Erythrocyte (RBC)‐Released ATP and Vascular Control: When it Works and What if it Does Not?

Substantial evidence suggests that RBCs contribute to matching of oxygen (O 2 ) supply with demand via release of small amounts of ATP in regions of increased O 2 need, enhancing blood flow appropriately. We simulated this system using a computational model incorporating network geometry and conducted signaling to predict microvascular flow responses to changes in tissue O 2 . To test this innovative model, we used Zucker Diabetic Fatty (ZDF) rats at 7 weeks (pre‐diabetes; high insulin, normal glucose) and at 12 weeks (type II diabetes [DMII]; normal insulin, high glucose). In pre‐diabetes, capillary O 2 supply was decreased without a decrease in capillary density. RBCs exposed to pre‐diabetic insulin levels (1 nM) did not release ATP in response to reduced O 2 and isolated arterioles perfused with insulin treated RBCs did not dilate in response to low extraluminal O 2 . Finally, RBCs of rats and humans with DMII did not release ATP when exposed to low O 2 and isolated arterioles perfused with RBCs of humans with DMII did not dilate in response to low O 2 . These findings in the intact microcirculation and isolated vessels are consistent with predictions of the computational model. This systems biology approach provides novel insights into the mechanisms by which O 2 supply is matched with O 2 demand and will enhance our understanding of the causes of peripheral vascular complications in pre‐ and type II diabetes. (NIH R33 HL089094 )