In vivo and electron microscopic study of the development of cerebral diabetic microangiography

The cerebral microvasculature of rats rendered diabetic with streptozotocin (75 mg/kg) and vehicle-treated controls paired for age and sex were studied using in vivo and electron microscopic methods at intervals from two weeks to 12 months after induction of diabetes mellitus. By one month, the pial vessels of diabetics were dilated and tortuous; and, the vasoconstrictive responses of arterioles and venules to local increases of PO2 in the artificial CSF bathing these vessels was reduced as was the linear velocity of blood flow. Increased arterio-venous shunting also was observed. By five months the responsiveness to locally increased levels of PO2 was further reduced from control values of 49.9% +/- 5 (SEM) to 6.9% +/- 1.8 (SEM) in arterioles and from 11.5% +/- 2.1 (SEM) to 2.6% +/- 0.7 (SEM) in venules. No further significant change in responsiveness was measured from five to twelve months. At 5 months, the functional changes were no longer reversible; and focal changes were noted in the thickness and density of the vascular basement membrane. Astrocytic end feet were greatly swollen and contained mitochondria having longitudinal rearrangement of their cristae. Basement membranes contained nodules of electron-lucent material which impinged on degenerating smooth muscle cells, pericytes and astrocytes. In some sites these cells appeared to be replaced by an amorphous material laced with collagen fibrils. By 11 months, these focal lesions were more frequent and more pronounced. Additional cellular replacement had taken place which resulted in greatly widened basement membranes which varied in density and content. The ultrastructure of endothelial cells was not noticeably altered except for presence of numerous cytoplasmic vesicles. The tight interendothelial junctions appeared to be intact even though dramatic changes had taken place perivascularly. These architectural and functional changes in the microvasculature are suggested to result not only from metabolic defects in the vascular wall, but also as a response to a relative hypoxia of the brain during the diabetic state.