MECHANISMS OF HYPERTENSION-INDUCED NEUROVASCULAR DYSFUNCTION AND COGNITIVE IMPAIRMENT IN A MOUSE MODEL OF CHRONIC HYPOPERFUSION

Hypertension is a major risk factor for cerebral small vessel disease (cSVD) and vascular dementia, yet the cellular mechanisms linking chronic hypertension to neurovascular dysfunction and cognitive decline remain unclear. In particular, the contribution of microglial dysfunction to hypertension-associated hypoperfusion injury is poorly defined.

We established a chronic cerebral hypoperfusion model by subjecting transgenic renin overexpression mice (RenTg) to unilateral common carotid artery occlusion (UCCAO) for 14 days. RenTg mice developed hypertension as early as one month of age, with elevated plasma angiotensin II levels. Although overt vascular rarefaction emerged only in aged RenTg mice, cerebrovascular dysfunction preceded structural loss, as evidenced by impaired cerebral blood flow (CBF) regulation in response to isoflurane and hypercapnia.

Microglial depletion using the CSF1R inhibitor PLX3397 impaired cerebrovascular regulation without affecting systemic blood pressure, indicating a critical role for microglia in maintaining vascular reactivity. Following UCCAO, RenTg mice exhibited greater and sustained CBF reduction, accompanied by motor and cognitive deficits. Transcriptomic analyses revealed dysregulation of extracellular matrix and inflammatory pathways, with downregulation of homeostatic microglial genes. Flow cytometry demonstrated reduced Tmem119⁺ microglia and increased CD86⁺ activated microglia, consistent with a damage-associated microglial phenotype. Histological analyses further revealed ECM degradation, microvascular pathology, and blood–brain barrier disruption.

Together, these findings identify a microglia-centered mechanism linking chronic hypertension and hypoperfusion to neurovascular dysfunction and cognitive impairment.