title: IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.
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.
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Neurosurgery and Szentagothai Research Center, Medical School, University of Pecs, Pecs, 7624, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, 940 S.L. Young Blvd. Rm. 653 Oklahoma City, 73104, OK, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Ashpole
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center D-3100, Medical Center North, Nashville, TN, USA.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Noa M
authors.initials: NM
authors.lastname: Valcarcel-Ares
authors.affiliation: Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, 6720, Hungary.
authors.forename: Akos
authors.initials: A
authors.lastname: Menyhart
authors.affiliation: Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, 6720, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Farkas
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Neurosurgery and Szentagothai Research Center, Medical School, University of Pecs, Pecs, 7624, Hungary.|Department of Physiology, University of Oklahoma Health Sciences Center, 940 S.L. Young Blvd. Rm. 653 Oklahoma City, 73104, OK, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Neurosurgery and Szentagothai Research Center, Medical School, University of Pecs, Pecs, 7624, Hungary.|Department of Physiology, University of Oklahoma Health Sciences Center, 940 S.L. Young Blvd. Rm. 653 Oklahoma City, 73104, OK, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Pulmonology, 1125 Budapest, Diós árok 1/c Semmelweis University, Budapest, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001921:Brain / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000502:physiology; D000069336:Neurovascular Coupling / Q000235:genetics*; D009569:Nitric Oxide / Q000096:biosynthesis; D065852:Spatial Memory / Q000502:physiology
chemical_list: C519530:insulin-like growth factor-1, mouse; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I
keywords: Insulin-like growth factor-1; arachidonic acid metabolites; astrocyte; endothelial dysfunction; functional hyperemia; neurovascular uncoupling; nitric oxide; somatomedin C; vascular aging; vascular cognitive impairment