Abstract
Introduction: Stroke due to sickle cell disease is often attributed to large vessel involvement in the disorder. The role of cerebral microvascular disease in sickle cell disease has received little attention. In this study, we examined development of cerebral microvascular lesions in a mouse model of sickle cell disease. We focused on cerebral microhemorrhages, the neuropathologic substrate of cerebral microbleeds. Methods: We studied microvascular disease in a well-characterized mouse model of humanized transgenic sickle (HbSS-BERK) and control (HbAA-BERK) mice expressing >99% human sickle hemoglobin (Hb) and normal human HbA, respectively. HbSS-BERK express human α and βS globins on a mixed genetic background. HbAA-BERK mice express normal human α and βA globin thus producing only normal human hemoglobin A, on the same mixed genetic background as HbSS-BERK. Seven- to nine-month-old mice (N=18 HbSS, N=12 HbAA) were examined. We collected mouse brains and performed standard histology using Prussian blue staining to detect CMH formation at 20x magnification. The average number, total area, and size of Prussian blue-positive deposits were quantified. In separate studies, Toluidine Blue staining was used to identify mast cells. Results: HbSS mice showed approximately 70% more cerebral microhemorrhages than controls (mean±SE of 1.17± 0.22 vs 0.69±0.13 number/cm 2, p=0.04). Lesion size did not differ between HbSS and control mice. Activated mast cells were identified in HbSS mouse brain but not in control mice. Conclusions: In this mouse model of sickle cell disease, HbSS mice demonstrated significantly increased development of cerebral microhemorrhages. These findings emphasize the potential importance of cerebral microvascular disease in sickle cell disease. Cerebral mast cell activation in sickle cell disease may be a novel target for investigation.
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