Abstract Body: Introduction: Cerebrovascular pathologies leading to VCID are diverse, but preclinical models mainly rely on chronic hypoperfusion-mediated neuroinflammation in otherwise healthy animals. Since diabetes increases VCID risk, our first goal was to develop a multi-etiology model of VCID in diabetes. Given that endothelin-1 (ET-1) contributes to decreased cerebral blood flow in multiple dementia models and that ETAR-mediated senescence in brain microvascular endothelial cells, our second goal was to assess ETARs in this VCID model.
Methods: Control and diabetic male Wistar rats were subjected to sham or a novel VCID model of microemboli (ME) injection followed by unilateral common carotid artery occlusion (UCCAO). Animals were followed for 22 weeks by several behavioral tests. Hematoxylin/Eosin (HE) and Luxol-fast blue staining (LFB) were used to assess brain pathologies. ETAR, hypoxia, and senescence markers were assessed by immunoblotting and immunohistochemistry.
Results (Table): Tissue damage in the striatum was greater, and the corpus callosum myelination score was lower in the diabetic UCCAO+ME group. ETARs, hypoxia marker HIF1α, and senescence marker p21 levels were increased in the UCCAO+ME diabetic group; while ETBRs rather decreased. Open Field revealed anxiety-like behavior (a significant decrease in time spent and entry frequency at the center square) and an increase in overall inactivity of D UCCAO+ME at week 22. Novel object recognition test showed a distinctive decline in the recognition and discrimination indices in the D UCCAO+ME group compared to the BL D UCCAO+ME and WK22 D sham groups. Of note, these animals exhibited a depressive-like behavior with a much lower entry frequency to the novel arm of the Y-maze despite their normal motor function compared to other groups.
Conclusion: This multi-etiology model of VCID, especially in comorbid disease models, may serve as a more clinically relevant model of VCID. Given that post-mortem brain ET-1 levels correlate with tissue hypoxia and disease severity in patients with dementia, further understanding of the regulation and effects of cerebral microvascular ETAR in neurovascular dysfunction is likely to identify novel therapeutic targets.