Chronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice

Area of Science:

• Neuroscience
• Vascular Biology
• Genetics

Background:

• Vascular dementia, the second leading cause of dementia, has poorly understood progression mechanisms.
• Cerebrovascular damage significantly contributes to the development of vascular dementia.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying cerebrovascular damage in vascular dementia.
• To identify potential therapeutic targets for restoring cerebrovascular integrity and mitigating neuroinflammation.

Main Methods:

• Induction of bilateral common carotid artery stenosis in mice to impair cerebral blood flow.
• Single-cell transcriptomics and advanced imaging of the mouse cortex.
• In vitro human cell models and in vivo studies with EPAS1 inhibition.
• Correlation analysis in human subjects linking endothelial cell damage to cognitive function.

Main Results:

• Venous endothelial cells exhibit maladaptive structural changes and increased Epas1 expression under impaired blood flow.
• Low-oxygen conditions activate sustained EPAS1 signaling specifically in venous cells.
• EPAS1 inhibition ameliorates cerebrovascular abnormalities, reduces microglial activation, and improves cerebral perfusion markers.
• Elevated levels of damaged venous endothelial cells in humans correlate with white matter injury and cognitive decline.

Conclusions:

• Epas1 signaling in venous cells plays a critical role in the progression of cerebrovascular damage.
• EPAS1 represents a promising therapeutic target for vascular dementia.
• Restoring cerebrovascular integrity via EPAS1 modulation may mitigate neuroinflammation and improve cognitive function.