Journal
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
Volume 74, Issue 4, Pages 446-454Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/gly144
Keywords
Vascular aging; Remodeling; Vascular smooth muscle cell; IGF-1; Neuroendocrine aging; Hypertension
Categories
Funding
- American Heart Association
- National Institute on Aging [R01-AG055395, R01-AG047879, R01-AG038747]
- National Institute of Neurological Disorders and Stroke (NINDS) [R01-NS056218, R01-NS100782]
- National Center for Complementary and Alternative Medicine [R01-AT006526]
- National Heart, Lung and Blood Institute (NHLBI) [R01-HL-088105]
- NIA-supported Geroscience Training Program in Oklahoma [T32AG052363]
- NIA-supported Oklahoma Nathan Shock Center [3P30AG050911-02S1]
- NIH-supported Oklahoma Shared Clinical and Translational Resources [NIGMS U54GM104938]
- College of Medicine Alumni Association
- Hungarian Academy of Sciences Bolyai Research Scholarship [BO/00634/15]
- PTE AOK-KA [3/2016 04.01/F, NKFI-FK123798, UNKP-17-4-I-PTE-7]
- Oklahoma Center for the Advancement of Science and Technology
- Presbyterian Health Foundation
- EU-funded Hungarian grant [EFOP-3.6.1-16-2016-00008]
- Reynolds Foundation
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Clinical and experimental studies show that age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels promotes the pathogenesis of intracerebral hemorrhages, which critically contribute to the development of vascular cognitive impairment and disability in older adults. Yet, the mechanisms by which IGF-1 deficiency compromises structural integrity of the cerebral vasculature are not completely understood. To determine the role of IGF-1 deficiency in pathological remodeling of middle cerebral arteries (MCAs), we compared alterations in vascular mechanics, morphology, and remodeling-related gene expression profile in mice with liver-specific knockdown of IGF-1 (Igf1(f/f) + TBG-Cre-AAV8) and control mice with or without hypertension induced by angiotensin-II treatment. We found that IGF-1 deficiency resulted in thinning of the media and decreased wall-to-lumen ratio in MCAs. MCAs of control mice exhibited structural adaptation to hypertension, manifested as a significant increase in wall thickness, vascular smooth muscle cell (VSMC) hypertrophy, decreased internal diameter and up-regulation of extracellular matrix (ECM)-related genes. IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and dysregulated ECM remodeling, decreasing elastin content and attenuating adaptive changes in ECM-related gene expression. Thus, circulating IGF-1 plays a critical role in maintenance of the structural integrity of cerebral arteries. Alterations of VSMC phenotype and pathological remodeling of the arterial wall associated with age-related IGF-1 deficiency have important translational relevance for the pathogenesis of intracerebral hemorrhages and vascular cognitive impairment in elderly hypertensive patients.
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