IGF-1 Provides Protective Role in Arteriosclerotic Cerebral Small Vessel Disease

BACKGROUND: Hypertension and advanced age are risk factors for arteriosclerotic cerebral small vessel disease (cSVD), a common cause of vascular dementia in elderly individuals. Circulating IGF-1 (insulin-like growth factor 1) levels decrease with age and are linked to age-related cognitive impairment. This study assessed the relationship between serum IGF-1 and arteriosclerotic cSVD severity in patients and the therapeutic effects and underlying mechanisms of exogenous IGF-1 supplementation in a cSVD rat model. METHODS: Serum and MR images were collected from healthy subjects (n=26) and patients with arteriosclerotic cSVD (n=86). Stroke-prone renovascular hypertensive rats were used as cSVD animal models and subjected to the Morris water maze test, magnetic resonance imaging, immunohistochemistry, and biochemical analysis. hCMEC/D3 cells were utilized to validate the underlying mechanisms in vitro. RESULTS: Serum IGF-1 concentration was significantly reduced in patients and rats with arteriosclerotic cSVD. Lower serum IGF-1 was associated with an increased cSVD burden and cognitive impairment. Compared with cSVD rats, IGF-1-treated rats had lighter white matter lesions, greater global cerebral blood flow, greater cerebrovascular density, less blood-brain barrier leakage, and better cognitive function. In vitro, IGF-1 administration promoted endothelial proliferation, migration, tube formation, and barrier function. Mechanistically, IGF-1 exerts neuroprotective effects by activating the IGF-1R (IGF-1 receptor)/Wnt7b/β-catenin pathway in vivo and in vitro. CONCLUSIONS: Low serum IGF-1 was associated with greater arteriosclerotic cSVD severity. IGF-1 treatment improved cerebral perfusion, blood-brain barrier integrity, and cognitive function in cSVD rats by activating the IGF-1R/Wnt7b/β-catenin pathway, suggesting a potential therapeutic strategy for patients with arteriosclerotic cSVD, particularly those with low IGF-1 levels.