Nonperfusion of retina and choroid in transgenic mouse models of sickle cell disease

Purpose. To determine if vascular occlusion and nonperfusion is associated with the outer retinal atrophy, retinopathy, and choroidopathy (chorioretinopathy) that occurs in the α(H)β(S)[β(MDV)] and α(H)β(S)[α(MD)β(MDD)] transgenic mouse models of sickle cell disease. Methods. Mice from the α(H)β(S)[β(MDD)] and α(H)β(S)[α(MD)β(MDD)] transgenic mouse lines that express high levels of human β⁵ globin were anesthetized and administered horseradish peroxidase (HRP) intracardially. After 1 min, the animals were sacrificed, and the retina from one eye was excised, fixed, and developed in diaminobenzidine (DAB). The contralateral eye was fixed, embedded whole in glycol methacrylate, and HRP developed in 2.5 μm sections. Results. HRP reaction product (HRP-RP) and stained erythrocytes (RBCs) (due to endogenous peroxidase) were diffusely distributed within all vascular lumens in flatmount retinas from control animals (littermates homozygous for the mouse β(Major) deletion not expressing the β⁵ transgene). In 42.5% of the transgenic mice expressing β⁵ without any proliferative retinopathy, many blood vessels contained RBC plugs and lacked lumenal HRP-RP. In addition to packed RBCs, fibrin was sometimes present at sites of occlusion. In sections from whole eyes of the same animals, foci of photoreceptor degeneration were associated with areas of choriocapillaris nonperfusion (lumen that lacked HRP-PR). In areas with normal photoreceptors, the choriocapillaris appeared perfused (HRP-RP was present). In animals with proliferative chorioretinopathy, some neovascular formations lacked luminal HRP-RP, suggesting autoinfarction. Conclusions. Nonperfused retinal and choroidal vessels were observed in mice from the α(H)β(S)[β(MDD)] and (α(H)β(S)[α(MD)β(MDD)] lines without retinal and choroidal neovascularization. whereas, all mice with neovascularization had nonperfused areas. Furthermore, small foci of PR loss were associated with areas of nonperfused choriocapillaris. These results suggest that sickle cell-mediated vaso-occlusions are an initial event in the chorioretinopathy and outer retinal atrophy that occurs in these models.