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bioRxiv · 10.1101/2025.04.14.648770

Hypertension-Induced Neurovascular and Cognitive Dysfunction at Single-Cell Resolution

Pacholko, A. G.·Schaeffer, S. M.·Santisteban, M. M.·Wang, G.·Racchumi, G.·Faraco, G.·Anrather, J.·Iadecola, C.
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Abstract

Arterial hypertension is a leading cause of cognitive impairment, attributed to cerebrovascular insufficiency, blood-brain barrier disruption, and white matter damage. However, the molecular mechanisms by which hypertension affects brain cells remain unclear. Using scRNA-seq in a mouse model of hypertension induced by angiotensin II, we mapped neocortical transcriptomic changes before (3 days) and after (42 days) onset of neurovascular and cognitive deficits. Surprisingly, evidence of endothelial transport disruption and senescence, stalled oligodendrocyte differentiation, interneuronal hypofunction and network imbalance emerged after just 3 days. By 42 days, when cognitive impairment becomes apparent, deficits in myelination and axonal conduction, as well as neuronal mitochondrial dysfunction developed. These findings reveal a previously unrecognized early vulnerability of endothelial cells, interneurons, and oligodendrocytes, and provide the molecular bases for the subsequent neurovascular dysfunction and cognitive impairment in hypertension. In addition, the data constitute a valuable resource for future mechanistic studies and therapeutic target validation.

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Pacholko, A. G., Schaeffer, S. M., Santisteban, M. M., Wang, G., Racchumi, G., Faraco, G., Anrather, J., Iadecola, C.. 2025-04-19. Hypertension-Induced Neurovascular and Cognitive Dysfunction at Single-Cell Resolution. https://doi.org/10.1101/2025.04.14.648770

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