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 magnetic resonance 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. Human cerebral microvascular endothelial cell line was 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 (Wnt family member 7b)/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.