Cerebral arteries in mice with sickle cell disease are exposed to larger areas of low wall shear stress

Sickle cell anemia (SCA) is the most severe form of sickle cell disease and causes increased stroke risk, even in children. Hemodynamic mechanisms underlying cerebral vasculopathy remain unclear. To test the hypothesis that SCA causes disturbed flow and increased regions of low wall shear stress (WSS) in cerebral arteries, we combined high-frequency ultrasound, micro–computed tomography, and computational fluid dynamics (CFD) using mice that are homozygous sickle (SS) and heterozygous trait (AS) at 4, 12, and 24 weeks of age. At 12 weeks, common carotid artery diameters were 12.4 – 18.6% larger in SS mice (p < 0.02), but common carotid inflow, blood velocity, and WSS did not differ significantly between genotypes. SS cerebral arteries demonstrated branch- and age-specific reductions in velocities and volumetric flow were measured in SS cerebral arteries, particularly the middle cerebral artery (MCA), independent of common carotid artery inflow. Time-averaged mean-of-the-maximum velocity (TAMMV) was ~40–50% lower in the MCA of SS mice at 4 and 12 weeks (p < 0.03), and MCA volumetric flow was lower by 56–67% (p < 0.05). CFD models revealed more regions of low WSS (<5 dyn/cm²) in cerebral arteries of SS mice, even in straight regions of the arteries at 12 and 24 weeks. Our findings indicate that SCA reduces blood velocity and volumetric blood flow in the cerebral arteries while increasing endothelial exposure to pathological shear stress, providing a link between altered hemodynamics and arterial wall damage unique to sickle cell disease.