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

• Published in: Aging cell Vol. 14; no. 6; pp. 1034 - 1044
• Main Authors: Toth, Peter, Tarantini, Stefano, Ashpole, Nicole M., Tucsek, Zsuzsanna, Milne, Ginger L., Valcarcel‐Ares, Noa M., Menyhart, Akos, Farkas, Eszter, Sonntag, William E., Csiszar, Anna, Ungvari, Zoltan
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2015; John Wiley and Sons Inc
• Subjects: Aging; Aging - genetics; Aging - physiology; Animals; arachidonic acid metabolites; astrocyte; Brain - physiology; Cerebrovascular Circulation - physiology; Cognition Disorders - genetics; Cognition Disorders - physiopathology; Cognitive ability; Disease Models, Animal; endothelial dysfunction; functional hyperemia; Insulin-Like Growth Factor I - deficiency; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin‐like growth factor‐1; Male; Maze Learning - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microvessels - physiology; Neurovascular Coupling - genetics; neurovascular uncoupling; nitric oxide; Nitric Oxide - biosynthesis; Original; Rodents; somatomedin C; Spatial Memory - physiology; vascular aging; vascular cognitive impairment; arachidonic acid metabolites; nitric oxide; vascular aging; somatomedin C; Insulin-like growth factor-1; neurovascular uncoupling; vascular cognitive impairment; functional hyperemia; astrocyte; endothelial dysfunction
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12372

Summary 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 (Igf1f/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.