Journal
AGING CELL
Volume 14, Issue 6, Pages 1034-1044Publisher
WILEY
DOI: 10.1111/acel.12372
Keywords
arachidonic acid metabolites; astrocyte; endothelial dysfunction; functional hyperemia; Insulin-like growth factor-1; neurovascular uncoupling; nitric oxide; somatomedin C; vascular aging; vascular cognitive impairment
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Funding
- American Heart Association
- National Center for Complementary and Alternative Medicine [R01-AT006526]
- National Institute on Aging [R01-AG047879, R01-AG038747, R01-NS056218]
- Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center [P30 AG028718]
- Oklahoma Center for the Advancement of Science and Technology
- Bolyai Janos Research Scholarship of the Hungarian Academy of Sciences [BO/00327/14/5]
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Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.
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