IGF-1 Deficiency Promotes Pathological Remodeling of Cerebral Arteries: A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging

Gabor A. Fulop, Francisco I. Ramirez-Perez, Tamas Kiss, Stefano Tarantini, Marta Noa Valcarcel Ares, Peter Toth, Andriy Yabluchanskiy, Shannon M. Conley, Praveen Ballabh, Luis A. Martinez-Lemus, Zoltan Ungvari, Anna Csiszar

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)446-454
Number of pages9
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume74
Issue number4
DOIs
StatePublished - Mar 14 2019

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Cerebral Arteries
Cerebral Hemorrhage
Somatomedins
Middle Cerebral Artery
Extracellular Matrix
Blood Vessels
Hypertension
Vascular Smooth Muscle
Hypertrophy
Smooth Muscle Myocytes
Elastin
Mechanics
Transcriptome
Angiotensin II
Up-Regulation
Maintenance
Phenotype
Gene Expression
Liver

Keywords

  • Hypertension
  • IGF-1
  • Neuroendocrine aging
  • Remodeling
  • Vascular aging
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Cite this

IGF-1 Deficiency Promotes Pathological Remodeling of Cerebral Arteries : A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging. / Fulop, Gabor A.; Ramirez-Perez, Francisco I.; Kiss, Tamas; Tarantini, Stefano; Valcarcel Ares, Marta Noa; Toth, Peter; Yabluchanskiy, Andriy; Conley, Shannon M.; Ballabh, Praveen; Martinez-Lemus, Luis A.; Ungvari, Zoltan; Csiszar, Anna.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 74, No. 4, 14.03.2019, p. 446-454.

Research output: Contribution to journalArticle

Fulop, GA, Ramirez-Perez, FI, Kiss, T, Tarantini, S, Valcarcel Ares, MN, Toth, P, Yabluchanskiy, A, Conley, SM, Ballabh, P, Martinez-Lemus, LA, Ungvari, Z & Csiszar, A 2019, 'IGF-1 Deficiency Promotes Pathological Remodeling of Cerebral Arteries: A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 74, no. 4, pp. 446-454. https://doi.org/10.1093/gerona/gly144
Fulop, Gabor A. ; Ramirez-Perez, Francisco I. ; Kiss, Tamas ; Tarantini, Stefano ; Valcarcel Ares, Marta Noa ; Toth, Peter ; Yabluchanskiy, Andriy ; Conley, Shannon M. ; Ballabh, Praveen ; Martinez-Lemus, Luis A. ; Ungvari, Zoltan ; Csiszar, Anna. / IGF-1 Deficiency Promotes Pathological Remodeling of Cerebral Arteries : A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2019 ; Vol. 74, No. 4. pp. 446-454.
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abstract = "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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AU - Ramirez-Perez, Francisco I.

AU - Kiss, Tamas

AU - Tarantini, Stefano

AU - Valcarcel Ares, Marta Noa

AU - Toth, Peter

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AU - Conley, Shannon M.

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