title: IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.
abstract: Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.
authors.affiliation: 1] Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA [2] Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center, University of Pecs, Pecs, 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, Oklahoma, USA.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 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, Oklahoma, USA.
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitschelen
authors.affiliation: 1] Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center, University of Pecs, Pecs, Hungary [2] Department of Physiology, New York Medical College, Valhalla, New York, USA.
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
authors.affiliation: 1] Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA [2] The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: 1] Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA [2] Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center, University of Pecs, Pecs, Hungary [3] The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: 1] Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA [2] Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center, University of Pecs, Pecs, Hungary [3] The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000375:Aging / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D003704:Dementia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000276:immunology / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology*; D006973:Hypertension / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D020768:Middle Cerebral Artery / Q000503:physiopathology; D050052:TRPC Cation Channels / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D050052:TRPC Cation Channels; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I