Abstract WP320: Microemboli Model of Vascular Cognitive Impairment/Dementia (VCID) Presents With Long-Term Brain Tissue Hypoxia: Relevance to Endothelin-1 (ET-1)

Abstract

Diabetes doubles the risk of VCID but the underlying reasons remain unclear. Given that diabetes mediates early endothelial dysfunction and activates the ET system, post-mortem brain ET-1 levels correlate with tissue hypoxia and disease severity in patients with dementia, and microemboli (ME) are more common in diabetic individuals, the goals of the current study were to investigate 1) the relationship between the brain ET system, hypoxia and neuroinflammation in a clinically relevant model of VCID, and 2) the impact of improving endothelial function on the ET system. At 10 weeks after the onset of diabetes, control and diabetic rats received cholesterol crystal ME (40-70 μm) injections and were monitored for 16 weeks. Another cohort received isosorbide mononitrate (ISMN, 75 mg/kg/day) and cilostazol (CZL, 60 mg/kg/day). Behavioral tests included novel object recognition (NOR) and Y-maze. After termination, brain tissue levels of ET-1/ETA/ETB, hypoxia markers myelin-associated glycoprotein (MAG), proteolipid protein-1 (PLP-1) and hypoxia-inducible factor-1α (HIF-1α), and microglia activation were analyzed by ELISA and immunoblotting. Diabetic animals had baseline deficits in certain cognitive domains that progressively worsened and treatment with (ISMN/CZL) prevented decline in cognitive function. HIF-1α levels were higher and MAG levels were lower in the ME cohorts indicating tissue hypoxia. MAG/PLP-1 ratio was even lower in diabetic ME animals (Table 1). ISMN/CZL treatment reduced HIF1α levels in the brain. While there was no dramatic change in plasma and brain tissue ET-1 levels, brain ET-1 levels correlated with HIF-1α (r 2 =0.53, p=0.0073) and MAG/PLP (r 2 =0.45, p=0.0167) in this model of VCID. The causal relationship between ET-1 and brain hypoxia, as well as neuroinflammation, needs further investigation. Strategies to improve vascular function by modulation of the ET system blockade can be a preventive and therapeutic strategy for VCID.