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

Peter Toth, Stefano Tarantini, Nicole M. Ashpole, Zsuzsanna Tucsek, Ginger L. Milne, Noa M. Valcarcel-Ares, Akos Menyhart, Eszter Farkas, William E. Sonntag, Anna Csiszar, Zoltan Ungvari

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1034-1044
Number of pages11
JournalAging cell
Volume14
Issue number6
DOIs
Publication statusPublished - Dec 1 2015

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

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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    Toth, P., Tarantini, S., Ashpole, N. M., Tucsek, Z., Milne, G. L., Valcarcel-Ares, N. M., Menyhart, A., Farkas, E., Sonntag, W. E., Csiszar, A., & Ungvari, Z. (2015). IGF-1 deficiency impairs neurovascular coupling in mice: Implications for cerebromicrovascular aging. Aging cell, 14(6), 1034-1044. https://doi.org/10.1111/acel.12372