Abstract
The incidence of vascular cognitive impairment is increased 2-3 folds in type 2 diabetes, but the underlying mechanisms have not been fully elucidated. The present study examines whether chronic hyperglycemia and associated enhanced ROS production damage cerebral vascular smooth muscle cells (VSMCs) that promote impairment of cerebral autoregulation and contribute to cognitive deficits. The levels of glucose (422 ± 32 vs. 94 ± 3 mg/dL) and glycated hemoglobin (HbA1c, 11.5 ± 0.2 vs. 4.3 ± 0.1%) were higher in old (12-month) T2DN (n=15) in comparison with SD control rats (n=6). We found that the actin cytoskeleton was disorganized in VSMCs freshly isolated from middle cerebral arteries (MCAs) of T2DN compared with SD rats, similar to what was seen in normal primary VSMCs treated with high glucose or H 2 O 2 . Superoxide production was elevated in VSMCs and MCAs freshly isolated from diabetic rats. Elderly diabetic rats exhibit impaired myogenic response of MCA. Cortical blood flow measured by laser Doppler flowmetry rose by 137 ± 15% vs. 36 ± 5% in diabetic (n=6) vs. normal rats (n=6) when MAP was increased from 100 to 180 mmHg. T2DN rats exhibited higher levels of IL-1 β and IL-2, and marked neurodegeneration in the hippocampus and cortex. Elderly T2DN rats showed learning and memory impairments using 8-arm water maze testing. These results indicate that hyperglycemia and elevated ROS production induce VSMCs dysfunction in diabetic rats, which contribute to cerebral vascular dysfunction and promote development of cognitive deficits.
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