IGF-1 Deficiency Promotes Pathological Remodeling of Cerebral Arteries: A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging.
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 (Igf1f/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.
['Fulop|Gabor A|GA|', 'Ramirez-Perez|Francisco I|FI|', 'Kiss|Tamas|T|', 'Tarantini|Stefano|S|', 'Valcarcel Ares|Marta Noa|MN|', 'Toth|Peter|P|', 'Yabluchanskiy|Andriy|A|', 'Conley|Shannon M|SM|', 'Ballabh|Praveen|P|', 'Martinez-Lemus|Luis A|LA|', 'Ungvari|Zoltan|Z|', 'Csiszar|Anna|A|']
D000375:Aging D000804:Angiotensin II D000818:Animals D002536:Cerebral Arteries D002543:Cerebral Hemorrhage D004195:Disease Models, Animal D006973:Hypertension D007334:Insulin-Like Growth Factor I D008297:Male D051379:Mice D008810:Mice, Inbred C57BL
IGF-1 Remodeling Hypertension Vascular smooth muscle cell Neuroendocrine aging Vascular aging