Related Experiment Video
Updated: May 5, 2026
Adult Mouse Venous Hypertension Model: Common Carotid Artery to External Jugular Vein Anastomosis.
Published on: January 27, 2015
Chronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice
Vanessa Kristina Wazny1,2, Aparna Mahadevan1, Nhi Nguyen1
1Neuroscience & Mental Health Program, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Abstract:
Vascular dementia is the second most common form of dementia. Yet, the mechanisms by which cerebrovascular damage progresses are insufficiently understood. Here, we create bilateral common carotid artery stenosis in mice, which effectively impairs blood flow to the brain, a major cause of the disease. Through imaging and single-cell transcriptomics of the mouse cortex, we uncover that blood vessel venous cells undergo maladaptive structural changes associated with increased Epas1 expression and activation of developmental angiogenic pathways. In a human cell model comparing arterial and venous cells, we observe that low-oxygen condition leads to sustained EPAS1 signaling specifically in venous cells. EPAS1 inhibition reduces cerebrovascular abnormalities, microglial activation, and improves markers of cerebral perfusion in vivo. In human subjects, levels of damaged endothelial cells from venous vessels are correlated with white matter injury in the brain and poorer cognitive functions. Together, these findings indicate EPAS1 as a potential therapeutic target to restore cerebrovascular integrity and mitigate neuroinflammation.
Insights
Vascular dementia mechanisms are unclear. This study reveals venous cell changes driven by Epas1 (Endothelial PAS domain-containing protein 1) signaling, offering a therapeutic target for brain blood flow and cognitive health.
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.
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