title: IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis.
abstract: Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1f/fmice crossed with mice expressing albumin-driven Cre recombinase). This model exhibits low-circulating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from those in mice with adult-onset IGF-1 deficiency (TBG-Cre-AAV8-mediated knockdown of IGF-1 at 5 month of age in Igf1f/fmice). Using a novel computational approach, we identified miRNA target genes that are co-expressed with IGF-1 and associate with aging and vascular pathophysiology. We found that among the predicted targets, the expression of multiple extracellular matrix-related genes, including collagen-encoding genes, were downregulated in mice with developmental IGF-1 deficiency. Collectively, IGF-1 deficiency during a critical period during early in life results in persistent changes in post-transcriptional miRNA-mediated control of genes critical targets for vascular health, which likely contribute to the deleterious late-life cardiovascular effects known to occur with developmental IGF-1 deficiency.
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: Stefano
authors: S
authors: Tarantini
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, Oklahoma City, OK, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors: Cory B
authors: CB
authors: Giles
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, Oklahoma City, OK, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors: Jonathan D
authors: JD
authors: Wren
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors: Nicole M
authors: NM
authors: Ashpole
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors: M Noa
authors: MN
authors: Valcarcel-Ares
authors: Reynolds Institute on Aging and Department of Geriatrics, University of Arkansas for Medical Science, 4301 West Markham Street, No. 748, Little Rock, AR, 72205, USA.
authors: Jeanne Y
authors: JY
authors: Wei
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors: William E
authors: WE
authors: Sonntag
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors: Zoltan
authors: http://orcid.org/0000-0002-6035-6039
authors: Z
authors: Ungvari
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. anna-csiszar@ouhsc.edu.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. anna-csiszar@ouhsc.edu.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. anna-csiszar@ouhsc.edu.
authors: Anna
authors: A
authors: Csiszar
mesh_terms: D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000502:physiology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D007334:Insulin-Like Growth Factor I
keywords: Epigenetics; Insulin-like growth factor 1; Post-transcriptional regulation; miRNA; microRNA