Sickle cell disease (SCD) is a genetic blood disorder affecting 100,000 Americans. People living with SCD experience deteriorating disease progression with accelerated damage to carotid and cerebral arteries occurring as early as 2 years old. 11% of children with SCD suffer an overt stroke and 37% will suffer a silent stroke. Hematopoietic stem cell transplant (HSCT) is currently the only known cure for SCD. Children may continue to be at risk for strokes and other complications after HSCT. The pathogenesis of how arterial damage is initiated, and progresses is not fully understood. Recent studies have shown using a humanized sickle cell transgenic mouse model that cathepsin K, a powerful protease, is upregulated in SCD and mediates elastin and collagen degradation in the arterial wall. In those studies, expansive remodeling was observed in the common carotid arteries associated with aneurysms and weakened artery mechanics. The central hypothesis of this proposal is that chronic inflammation in SCD stimulates cathepsin K overexpression leading to pathological expansive arterial remodeling that can cause accelerated progression of aneurysms and hemorrhagic strokes. To analyze the mechanisms that cause arterial damage in SCD, a combination of both in-vitro and in-silico studies will be used to investigate the morphology and hemodynamics of carotid arteries in mice with SCD. In this longitudinal study, a label free magnetic resonance angiography method will be used for the quantification of morphological changes to carotid and cerebral arteries in SCD mice as they age thereby reducing subject variability. The objective of this proposal is to use magnetic resonance angiography to (1) determine the role of cathepsin K in expansive arterial remodeling using sickle cell transgenic mice genetically null for cathepsin K, (2) determine the effect of curative HSCT in preventing arteriopathy in SCD, and (3) identify pathological fluid flow profiles that would indicate arterial damage in SCD in an age-dependent manner. This research will provide a foundation for understanding cathepsin-mediated arterial remodeling and to determine why arterial damage persists in some patients after HSCT. These studies will potentially help develop novel therapies to prevent arteriopathy and strokes in SCD.