IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z
Aging Cell. 2015 14 (6): 1034-44

PMID: 26172407 · PMCID: PMC4693458 · DOI:10.1111/acel.12372

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.

© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

MeSH Terms (16)

Aging Animals Brain Cerebrovascular Circulation Cognition Disorders Disease Models, Animal Insulin-Like Growth Factor I Male Maze Learning Mice Mice, Inbred C57BL Mice, Knockout Microvessels Neurovascular Coupling Nitric Oxide Spatial Memory

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