Experimental models of cerebral small vessel disease: Physiological constraints, translational challenges and future directions.

Cerebral small vessel disease (cSVD) is a chronic, progressive cerebrovascular disorder and the second most common cause of dementia after Alzheimer's disease. It accounts for approximately 20% of strokes, including a quarter of ischaemic strokes and nearly half of vascular dementias, representing a growing clinical and socio-economic burden in ageing populations. Despite its prevalence, mechanistic understanding remains limited and disease-modifying therapies are lacking. A major obstacle is the difficulty of interrogating disease progression in vivo, as the small calibre and deep location of affected vessels restrict assessment. Experimental modelling has therefore been central to advancing cSVD research. Rodent models have provided insight into vascular dysfunction, white matter injury and blood-brain barrier (BBB) impairment, but differ from humans in cerebrovascular anatomy, cellular composition and disease trajectory. Emerging in vitro approaches, including three-dimensional cultures and microfluidic systems incorporating human vascular cells, offer improved experimental control and translational relevance, yet struggle to capture the slow progression of cSVD and its comorbidities such as hypertension and ageing. Most models therefore isolate pathological features rather than reproducing the integrated physiology of disease. In this review, we critically evaluate current in vivo, in vitro and in silico models of cSVD, highlighting their strengths and limitations. We identify the glymphatic system and brain clearance as underexplored but potentially unifying pathways linking vascular dysfunction, perivascular-space enlargement and impaired fluid clearance. Incorporating glymphatic elements into advanced models may address key mechanistic gaps. Improving physiological fidelity in cSVD modelling will be essential for robust target identification and development of effective therapies.