title: Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype.
abstract: Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1f/f+ TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF-1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high-risk elderly patients.
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Noa M
authors.initials: NM
authors.lastname: Valcarcel-Ares
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Yabluchanskiy
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Springo
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Gabor A
authors.initials: GA
authors.lastname: Fulop
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ashpole
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Cory B
authors.initials: CB
authors.lastname: Giles
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005684:Gait; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D018384:Oxidative Stress; D010641:Phenotype; D011597:Psychomotor Performance
chemical_list: C519530:insulin-like growth factor-1, mouse; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D020782:Matrix Metalloproteinases; D019331:NG-Nitroarginine Methyl Ester
keywords: arteriole; dementia; gait dysfunction; microbleed; oxidative stress