Shear-Sensitive Regulation of Neutrophil Flow Behavior and Its Potential Impact on Microvascular Blood Flow Dysregulation in Hypercholesterolemia

Objective— Shear stress–induced pseudopod retraction is an anti-inflammatory measure that minimizes neutrophil activity and is regulated by membrane cholesterol. We tested the hypothesis that a hypercholesterolemic impairment of shear mechanotransduction alters the neutrophil flow behavior leading to microvascular dysfunction. Approach and Results— We examined the shear effects on the flow behavior of human leukocytes. When subjected to shearing during cone-plate viscometry, leukocyte suspensions exhibited parallel time-dependent reductions in viscosity and pseudopod activity. Shear-induced reductions in suspension viscosity were attenuated by membrane cholesterol enrichment. We also showed that enhanced pseudopod activity of leukocyte suspensions in 10% hematocrit significantly ( P P r =0.4 and r =−0.3, respectively) with neutrophil shear responsiveness and were abrogated by neutropenia. Conclusions— These results provide the first evidence that the neutrophils contribute to tissue blood flow autoregulation. Moreover, a deficit in the neutrophil responsiveness to shear may be a feature of hypercholesterolemia-related microvascular dysfunction.