Chronic Cerebral Hypoperfusion Induces Pathological Venous Remodeling via EPAS1 Regulation

Chronic cerebral hypoperfusion, induced by bilateral common carotid artery stenosis (BCAS), models the underlying cause of vascular dementia. We used single-cell transcriptomics to identify endothelial subtype-specific responses to BCAS in the mouse prefrontal cortex. The most dynamic molecular changes were observed in venous endothelial cells, with upregulated pathways linked to vascular remodeling and angiogenesis. Cerebral hypoperfusion upregulated expression of the endothelial PAS domain protein 1 (Epas1 ) gene in venous endothelial cells, while exposure of human venous endothelial cells to 1% oxygen in vitro caused sustained nuclear translocation of EPAS1. Pharmacological inhibition of EPAS1 reduced abnormal venous sprouting and concomitantly dampened microglia activation. Among human subjects with mild cerebrovascular disease, there was a negative correlation observed between their circulating damaged endothelial cells (CECs) and cerebral blood flow levels. In addition, elevated levels of venous-origin CECs were detected in subjects with white matter lesions and were notably linked to poorer overall cognitive function. We conclude that venous endothelial cells are potential therapeutic targets for vessel normalization to mitigate vascular cognitive impairment caused by chronic cerebral hypoperfusion.