Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD), plaguing the elderly population. Although there is no definitive pathological definition of VCI, it is generally accepted that VCI results in global and/or local cerebral hypoperfusion, leading to cortical and subcortical infarcts and white matter lesions (WMLs). The integrity of white matter is critical in regulating efficient neuronal communication and maintaining cognitive function. Chronic cerebral hypoperfusion-induced WMLs are now considered a key mechanism leading to VCI and dementia. However, the mechanism underlying WMLs in response to hypoperfusion has not yet been fully clarified. Recent studies have shown that the dysfunction of pericytes is related to diverse vascular disorders, such as stroke and AD. Yet, the pathological event bridging pericyte dysfunction and cognitive impairment in VCI is unexplored. In this study, we aimed to investigate whether pericyte dysfunction could affect WMLs and cognitive impairment in a rat VCI model. Using a rat model of chronic cerebral hypoperfusion-induced VCI by two-vessel occlusion (2VO), we confirmed that 2VO could induce WMLs and cognitive impairment. We found that the number of pericytes in the brain was significantly altered after 2VO. Furthermore, we found that the capillary constrictions at pericyte bodies were significantly increased in the brain after 2VO compared to sham-operated rats, along with reduced cerebral blood flow (CBF). We then asked whether manipulating pericyte function could affect WMLs and cognitive impairment in VCI rats. CGS21680, a specific adenosine A2A subtype receptor agonist, has previously shown the effect of vasodilation. We intranasally administered CGS21680 twice per day for 7 days and found that the rats treated with CGS21680 showed a significant CBF increase at 7 and 14 days after 2VO, compared to the vehicle group, along with an increase in capillary lumens beneath pericytes after the treatment. Importantly, WMLs and cognitive impairment were significantly improved after CGS21680 treatment compared to the vehicle group. Our data suggest that pericyte dysfunction plays a critical role in WMLs and cognitive impairment in the rat model of VCI, which will help us further understand the pathogenesis and develop targeted interventions for VCI.