Therapeutic strategies in vascular cognitive impairment: Insights from the bilateral common carotid artery stenosis mouse model.

Vascular cognitive impairment (VCI) is a major consequence of cerebrovascular disease, but disease-modifying therapies remain limited. Chronic cerebral hypoperfusion is increasingly recognized not simply as reduced cerebral blood flow, but as a sustained disturbance of oxygen delivery, capillary perfusion, neurovascular coupling, blood-brain barrier integrity, glial homeostasis, white matter maintenance, and synaptic network function. The bilateral common carotid artery stenosis (BCAS) mouse model is a central experimental platform for studying hypoperfusion-related VCI, as it exhibits reproducible cerebral blood flow reduction, white matter pathology, gliovascular injury, and cognitive impairment while permitting genetic manipulation, longitudinal imaging, retinal readouts, omics profiling, and therapeutic testing. This review synthesizes therapeutic studies in BCAS model mice across vascular/endothelial and hemodynamic mechanisms, oxidative and ferroptotic stress, ion-water transport, neuronal excitability and synaptic support, remote ischemic conditioning, regenerative and cell-based approaches, and biomarker-driven model refinement. Across these domains, successful interventions frequently converge on interconnected network nodes rather than isolated linear pathways, linking endothelial function, blood-brain barrier stability, redox-lipid balance, astrocytic ion-water regulation, microglial repair states, oligodendrocyte maturation, myelin integrity, and circuit plasticity. However, methodological heterogeneity concerning surgery, animal characteristics, behavioral testing, treatment timing, and outcome selection restricts translation. Future BCAS studies should prespecify treatment windows, particularly delayed-treatment paradigms initiated after objectively documented hypoperfusion, white matter injury, or cognitive impairment. Studies should also incorporate systemic dose-response assessments, biomarker-guided treatment stratification, clinically relevant comorbidities, and rational combination therapies. Such approaches may convert mechanistic insights from chronic hypoperfusion models into clinically credible therapeutic strategies for VCI.