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Published on: June 22, 2013
Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats
Siyang Lin1, Benjamin Landon1, Hongxia Zhang2
1Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Abstract:
Vascular cognitive impairment (VCI) encompasses cognitive disorders associated with cerebrovascular disease, often manifesting as white matter lesions (WMLs), irrespective of precise triggers. The integrity of white matter is essential for neural communication and cognitive function maintenance. Persistent cerebral hypoperfusion-induced WMLs are now acknowledged as a key driver of VCI and dementia, though their exact formation mechanism remains unclear. Recent studies link pericyte dysfunction to diverse brain disorders like Alzheimer disease. However, the exact pathological connection between pericyte dysfunction and cognitive impairment in VCI remains unexplored. In this study, we aimed to examine whether pericyte dysfunction could impact WMLs and cognitive impairment in a rat VCI model. Using a rat model of chronic cerebral hypoperfusion-induced VCI through two-vessel occlusion (2VO), we verified that 2VO induced both WMLs and cognitive impairment. Notably, the number of pericytes in the brain was significantly altered after 2VO. Furthermore, we observed significantly increased capillary constrictions at pericyte bodies in the brains of 2VO-induced rats compared to sham-operated rats, accompanied by reduced cerebral blood flow (CBF). To tackle this issue, we administered CGS21680, a specific adenosine A2A subtype receptor agonist, intranasally twice a day for 7 days. We found that rats treated with CGS21680 exhibited a significant increase in CBF at 7 and 14 days after 2VO, compared to the vehicle group. Moreover, capillary lumens beneath pericytes also increased after the CGS21680 treatment. Importantly, the treatment led to substantial improvements in WMLs and cognitive impairment compared to the vehicle group. Our findings suggest a critical role of pericyte dysfunction in WMLs and cognitive impairment within the rat VCI model. This insight contributes to our understanding of pathogenesis and offers prospects for targeted intervention in VCI.
Insights
Pericyte dysfunction contributes to white matter lesions and cognitive decline in vascular cognitive impairment (VCI). Adenosine A2A receptor agonist treatment improved cerebral blood flow, reduced lesions, and enhanced cognition in a rat VCI model.
Area of Science:
- Neuroscience
- Cerebrovascular Disease Research
- Cognitive Impairment Studies
Background:
- Vascular cognitive impairment (VCI) is linked to white matter lesions (WMLs) driven by chronic cerebral hypoperfusion.
- Pericyte dysfunction is implicated in various brain disorders, but its role in VCI pathogenesis is unclear.
- Understanding the mechanisms of WMLs and cognitive deficits in VCI is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of pericyte dysfunction in white matter lesions (WMLs) and cognitive impairment in a rat model of vascular cognitive impairment (VCI).
- To explore the potential therapeutic effects of an adenosine A2A receptor agonist on pericyte function, cerebral blood flow, WMLs, and cognitive deficits in VCI.
Main Methods:
- A rat model of chronic cerebral hypoperfusion was induced using two-vessel occlusion (2VO).
- Pericyte number, capillary constriction, and cerebral blood flow (CBF) were assessed in 2VO-induced rats.
- An adenosine A2A receptor agonist (CGS21680) was administered intranasally to assess its impact on VCI parameters.
Main Results:
- The 2VO model successfully induced WMLs and cognitive impairment in rats.
- 2VO led to altered pericyte numbers, increased capillary constrictions, and reduced CBF.
- CGS21680 treatment significantly increased CBF, improved capillary lumens, reduced WMLs, and ameliorated cognitive deficits.
Conclusions:
- Pericyte dysfunction plays a critical role in the development of WMLs and cognitive impairment in the context of chronic cerebral hypoperfusion.
- Targeting adenosine A2A receptors with agonists like CGS21680 shows therapeutic potential for VCI by improving cerebral hemodynamics and neuronal function.
- These findings offer new insights into VCI pathogenesis and suggest novel strategies for intervention.
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