Vasculopathy in the Forecast: Biophysically Altered Red Cells Act as Hemodynamic Hail to Trigger Endothelial Dysfunction.

Beyond mere gas exchange, erythrocytes significantly influence vascular health and inflammation. For example, in sickle cell disease (SCD), microvascular occlusion due to abnormal red blood cells (RBCs) and hemolysis are known to cause endothelial dysfunction. However, this model fails to explain the chronic vasculopathy found throughout the entire circulation or the cardiovascular complications associated with iron deficiency anemia (IDA), suggesting additional mechanisms at play. Here we propose a paradigm shift: that the biophysical alterations of erythrocytes-such as reduced cell deformability and altered size-are, in and of themselves, sufficient to induce widespread endothelial dysfunction via mechanisms that are entirely independent of cell adhesion, hemolysis, or vascular obstruction. Through the fluid dynamic phenomenon of cell margination, aberrant RBCs invade the protective cell-free layer, leading to physical interactions with the endothelium that ultimately directly induce vascular pathology. These brief collision-like events and resulting high-magnitude transient fluctuations in local wall shear stress serve as potent mechanobiological stimuli. Physically, these pathologic RBCs are like hailstones, compared to the much softer and deformable snowflake-like healthy RBCs. The endothelium, acting as the "roof" that is constantly and chronically pummeled and pelted by the "hailstorm" of these pathologic RBCs, physiologically responds to these purely physical interactions via mechanotransduction that, in turn, induce proinflammatory signals. This Perspective synthesizes recent experimental and computational evidence across multiple disease states associated with RBC abnormalities, including SCD, IDA, and COVID-19, to reconsider the erythrocyte's biophysical properties not merely as disease biomarkers, but as primary and targetable mechanobiological drivers of vascular inflammation.