Chronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice

Vanessa Kristina Wazny, Aparna Mahadevan, Nhi Nguyen, Hannah Wee, Ashwati Vipin, Tammy Lam, Kai Yi Tay, Jia-Xiang See, Gurveen Sandhu, Yi Jin Leow, Giuseppe D’Agostino, Martin Graf, Aravind Sivakumar, Sichen Lin, Nguyen Cao Thien Phuc, James Xiao Yuan Chen, Sarah R. Langley, Lay Teng Ang, Kyle M. Loh, Nagaendran Kandiah, George J. Augustine and Christine Cheung ()
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Vanessa Kristina Wazny: Nanyang Technological University
Aparna Mahadevan: Nanyang Technological University
Nhi Nguyen: Nanyang Technological University
Hannah Wee: Nanyang Technological University
Ashwati Vipin: Nanyang Technological University
Tammy Lam: Nanyang Technological University
Kai Yi Tay: Nanyang Technological University
Jia-Xiang See: Nanyang Technological University
Gurveen Sandhu: Nanyang Technological University
Yi Jin Leow: Nanyang Technological University
Giuseppe D’Agostino: Nanyang Technological University
Martin Graf: Nanyang Technological University
Aravind Sivakumar: Agency for Science, Technology and Research
Sichen Lin: Nanyang Technological University
Nguyen Cao Thien Phuc: Nanyang Technological University
James Xiao Yuan Chen: Nanyang Technological University
Sarah R. Langley: Cardiff University
Lay Teng Ang: Stanford University
Kyle M. Loh: Stanford University
Nagaendran Kandiah: Nanyang Technological University
George J. Augustine: Nanyang Technological University
Christine Cheung: Nanyang Technological University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61614-3

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