Beyond oxygen transport: red blood cells as emerging players in mediating endothelial dysfunction in diabetes

Endothelial dysfunction, a hallmark of diabetic vascular complications, is thought to arise from hyperglycemia-induced oxidative stress and inflammation within endothelial cells. However, accumulating evidence suggests that red blood cells (RBCs), beyond serving as passive oxygen carriers, actively contribute to vascular pathology by communicating detrimental changes to the endothelium eliciting endothelial dysfunction.

This review critically evaluates the mechanistic role of RBCs in mediating endothelial dysfunction in diabetes, focusing on three key questions. First, what pathological alterations occur in diabetic RBCs that promote endothelial dysfunction? Key diabetes-induced changes within RBCs that have been implicated in endothelial dysfunction include enhanced arginase-1 activity, RBC eNOS uncoupling, glycation-induced structural modifications structural modifications (e.g. reduced deformability and increased aggregation), shedding of pathological extracellular vesicles (RBC-EVs), and loss of protective signals such as ATP and MicroRNAs (e.g. miR-210 and miR-210-3p). Second, how do anucleate RBCs acquire these pathological alterations? In addition to the direct metabolic effects of hyperglycemia, we discuss other possibilities including bidirectional vesicular exchange between RBCs and endothelial cells. Third, how are these pathological signals transmitted from RBCs to the endothelium? We discuss four possible routes of communication including direct ligand-receptors interactions, paracrine signaling, direct physico-mechanical perturbations, and vesicular transport via RBC-EVs.

Diabetes induces many pathological alterations within RBCs which have been shown to be transmitted to endothelial cells and elicit endothelial dysfunction. The role of RBCs as key players in eliciting endothelial dysfunction represent a major paradigm shift in our understanding of diabetes-induced vascular dysfunction and thus, RBCs might represent a novel therapeutic target in cardiovascular disease.