Animal models of ischemic cerebral small vessel disease: A narrative review of pathological phenotypes, challenges, and future directions.

Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment and stroke, yet its pathophysiology remains incompletely understood and effective treatments are lacking. This narrative review focuses on animal models that recapitulate the ischemic phenotypes of CSVD, including white matter lesions, lacunar infarcts, and chronic cerebral hypoperfusion; hemorrhagic CSVD subtypes are not discussed. We systematically survey the principal model categories for CSVD, encompassing chronic hypoperfusion models (such as bilateral common carotid artery stenosis [BCAS]), hypertensive models (such as spontaneously hypertensive rats [SHR]), genetically engineered models (such as CADASIL and CARASIL models), and chemically induced models (such as local injection of L-NIO). The article elaborates on the principles underlying the establishment of each model type, the pathological phenotypes simulated (vascular injury, white matter lesions, microinfarcts, microhemorrhages, neurological deficits), and their respective advantages and disadvantages. Building on this foundation, we have focused on analyzing the common challenges and controversies faced by existing models, including clinical relevance (species differences), pathological complexity (multifactorial integration), and the simulation of chronic processes. Finally, this review summarizes universal criteria for model evaluation and outlines future directions, emphasizing the integration of multifactorial composite models and the use of novel technologies such as large animals and organoids. These insights provide systematic guidance for bridging the gap between basic science and translational medicine in CSVD.