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

6 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    Fulop, G. A., Ramirez-Perez, F. I., Kiss, T., Tarantini, S., Valcarcel Ares, M. N., Toth, P., Yabluchanskiy, A., Conley, S. M., Ballabh, P., Martinez-Lemus, L. A., 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, 74(4), 446-454. https://doi.org/10.1093/gerona/gly144