Sex-divergent neurovascular and cognitive effects of chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion is the leading risk factor for the development of vascular dementia and is associated with white matter damage and cognitive impairment. Here, we assessed sex differences in vascular and neural pathology and cognitive impairment in the asymmetric carotid arterial stenosis (ACAS) mouse model of chronic cerebral hypoperfusion. Thirty days of ACAS significantly reduced cerebral blood flow, increased microvascular permeability as evidenced by extravasation of IgG and fibrinogen into brain parenchyma, and impaired MCA vasodilation. ACAS also induced white matter damage in the hippocampus and corpus callosum, with greater damage in the corpus callosum of females compared to males. Spatial memory impairments on the Barnes maze were significantly greater in ACAS males than in females. Finally, miRNA analyses revealed upregulated angiogenic miRNA in the hippocampus and cortex in ACAS females and upregulated neuroinflammatory miRNA in the hippocampus and cortex in ACAS males. Together, these findings indicate that the ACAS model produces robust neuropathology and sex differences in spatial memory and miRNA profiles.