IGF ‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging
Péter Tótha b c d, Stefano Tarantinib d e f, Nicole M. Ashpoleb d, Zsuzsanna Tucsekb d, Ginger L. Milneg h, Marta Noa Valcarcel‐Aresb d, Ákos Menyhárti j, Eszter Farkasi j, William Edmund Sonntagb d k l, Anna Csiszára b c d e f k l✉, Zoltan I. Ungvaria b c d e f k l m✉
- aDepartment of Neurosurgery and Szentagothai Research Center Medical School University of Pecs Pecs 7624 Hungary
- bDonald W. Reynolds Department of Geriatric Medicine Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA
- cDepartment of Neurosurgery and Szentagothai Research Center, Medical School, University of Pecs, Pecs, 7624 Hungary
- dDonald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104 USA
- eDepartment of Physiology University of Oklahoma Health Sciences Center 940 S.L. Young Blvd. Rm. 653 Oklahoma City 73104 OK USA
- fDepartment of Physiology, University of Oklahoma Health Sciences Center, 940 S.L. Young Blvd. Rm. 653 Oklahoma City, 73104 OK, USA
- gDivision of Clinical Pharmacology Vanderbilt University Medical Center D‐3100 Medical Center North Nashville TN USA
- hDivision of Clinical Pharmacology, Vanderbilt University Medical Center D-3100, Medical Center North, Nashville, TN, USA
Papers open inside SciRah from the original publisher or repository; SciRah never hosts them.
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 (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.