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IGF-1 Provides Protective Role in Arteriosclerotic Cerebral Small Vessel Disease
Xiangming Xu1,2, Ming Yi1, Chi Xiao1
1Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases (X.X., M.Y., C.X., J.Y., J.G., W.Z., K.Z., L.H., L.L., Y.F.), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Insights
Low insulin-like growth factor 1 (IGF-1) levels are linked to severe arteriosclerotic cerebral small vessel disease (cSVD). IGF-1 supplementation improved brain function and reduced damage in a cSVD rat model, offering a potential therapy.
Area of Science:
- Neurology
- Endocrinology
- Vascular Biology
Background:
- Arteriosclerotic cerebral small vessel disease (cSVD) is a major cause of vascular dementia in the elderly.
- Hypertension and advanced age are key risk factors for cSVD.
- Decreased circulating insulin-like growth factor 1 (IGF-1) levels correlate with age-related cognitive decline.
Purpose of the Study:
- To investigate the association between serum IGF-1 levels and arteriosclerotic cSVD severity in patients.
- To evaluate the therapeutic potential of IGF-1 supplementation in a rat model of cSVD.
- To elucidate the underlying molecular mechanisms of IGF-1's neuroprotective effects.
Main Methods:
- Serum IGF-1 and MRI data were collected from healthy individuals and cSVD patients.
- A rat model of cSVD was established and treated with IGF-1.
- Behavioral tests (Morris water maze), MRI, immunohistochemistry, and in vitro cell assays were performed.
Main Results:
- Patients and rats with cSVD exhibited significantly lower serum IGF-1 concentrations.
- Lower IGF-1 levels correlated with increased cSVD burden and cognitive impairment.
- IGF-1 treatment in rats reduced white matter lesions, improved cerebral blood flow, enhanced blood-brain barrier integrity, and improved cognitive function.
Conclusions:
- Low serum IGF-1 is associated with increased severity of arteriosclerotic cSVD.
- IGF-1 therapy ameliorates cSVD-related brain damage and cognitive deficits in rats.
- The neuroprotective effects are mediated by the IGF-1 receptor (IGF-1R)/Wnt7b/β-catenin pathway, suggesting a therapeutic avenue for cSVD.
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.
