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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

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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 (Igf1 f/f mice 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 Igf1 f/f mice). 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.

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References

  • Alonso-Bouzon C, Carcaillon L, Garcia-Garcia FJ, Amor-Andres MS, El Assar M, Rodriguez-Manas L (2014) Association between endothelial dysfunction and frailty: the Toledo study for healthy aging. Age (Dordr) 36:495–505

    Article  CAS  Google Scholar 

  • Asada S, Takahashi T, Isodono K, Adachi A, Imoto H, Ogata T, Ueyama T, Matsubara H, Oh H (2008) Downregulation of dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis. Am J Physiol Heart Circ Physiol 295:H2512–H2521

    Article  CAS  PubMed  Google Scholar 

  • Ashpole NM, Herron JC, Mitschelen MC, Farley JA, Logan S, Yan H, Ungvari Z, Hodges EL, Csiszar A, Ikeno Y, Humphrey MB, and Sonntag WE (2015) IGF-1 regulates vertebral bone aging through sex-specific and time-dependent mechanisms. J Bone Miner Res 31(2):443–454

  • Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarcel-Ares MN, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A (2012a) Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol Biol Med Sci 67:313–329

    Article  CAS  Google Scholar 

  • Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, Ballabh P, Koller A, Farley JA, Sonntag WE, Csiszar A, Ungvari Z (2012b) Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol A Biol Sci Med Sci 67:553–564

    Article  PubMed  CAS  Google Scholar 

  • Bake S, Selvamani A, Cherry J, Sohrabji F (2014) Blood brain barrier and neuroinflammation are critical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats. PLoS One 9:e91427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Barker DJ (2004a) The developmental origins of adult disease. J Am Coll Nutr 23:588S–595S

    Article  CAS  PubMed  Google Scholar 

  • Barker DJ (2004b) Developmental origins of adult health and disease. J Epidemiol Community Health 58:114–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG (2005) Trajectories of growth among children who have coronary events as adults. N Engl J Med 353:1802–1809

    Article  CAS  PubMed  Google Scholar 

  • Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2:577–580

    Article  CAS  PubMed  Google Scholar 

  • Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr Top Dev Biol 63:189–225

    Article  CAS  PubMed  Google Scholar 

  • Bates DJ, Li N, Liang R, Sarojini H, An J, Masternak MM, Bartke A, Wang E MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging. Aging Cell 9:1–18

  • Bates DJ, Li N, Liang R, Sarojini H, An J, Masternak MM, Bartke A, Wang E (2010) MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging. Aging Cell 9:1–18

    Article  CAS  PubMed  Google Scholar 

  • Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE (2004) Developmental plasticity and human health. Nature 430:419–421

    Article  CAS  PubMed  Google Scholar 

  • Bidlingmaier M, Friedrich N, Emeny RT, Spranger J, Wolthers OD, Roswall J, Korner A, Obermayer-Pietsch B, Hubener C, Dahlgren J, Frystyk J, Pfeiffer AF, Doering A, Bielohuby M, Wallaschofski H, Arafat AM (2014) Reference intervals for insulin-like growth factor-1 (igf-i) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations. J Clin Endocrinol Metab 99:1712–1721

    Article  CAS  PubMed  Google Scholar 

  • Blakemore SJ, Burnett S, Dahl RE (2010) The role of puberty in the developing adolescent brain. Hum Brain Mapp 31:926–933

    Article  PubMed  PubMed Central  Google Scholar 

  • Blanton RE, Cooney RE, Joormann J, Eugene F, Glover GH, Gotlib IH (2012) Pubertal stage and brain anatomy in girls. Neuroscience 217:105–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boehm M, Slack F (2005) A developmental timing microRNA and its target regulate life span in C. elegans. Science 310:1954–1957

    Article  CAS  PubMed  Google Scholar 

  • Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S (2009) MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324:1710–1713

    Article  CAS  PubMed  Google Scholar 

  • Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, Kaluza D, Treguer K, Carmona G, Bonauer A, Horrevoets AJ, Didier N, Girmatsion Z, Biliczki P, Ehrlich JR, Katus HA, Muller OJ, Potente M, Zeiher AM, Hermeking H, Dimmeler S (2013) MicroRNA-34a regulates cardiac ageing and function. Nature 495:107–110

    Article  CAS  PubMed  Google Scholar 

  • Bruel A, Oxlund H (2002) Growth hormone influences the content and composition of collagen in the aorta from old rats. Mech Ageing Dev 123:627–635

    Article  CAS  PubMed  Google Scholar 

  • Carter CS, Ramsey MM, Sonntag WE (2002) A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan. Trends Genet 18:295–301

    Article  CAS  PubMed  Google Scholar 

  • Che P, Liu J, Shan Z, Wu R, Yao C, Cui J, Zhu X, Wang J, Burnett MS, Wang S (2014) miR-125a-5p impairs endothelial cell angiogenesis in aging mice via RTEF-1 downregulation. Aging Cell 13:926–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen L, Charrier A, Zhou Y, Chen R, Yu B, Agarwal K, Tsukamoto H, Lee LJ, Paulaitis ME, Brigstock DR (2014) Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology 59:1118–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen LJ, Chuang L, Huang YH, Zhou J, Lim SH, Lee CI, Lin WW, Lin TE, Wang WL, Chen L, Chien S, Chiu JJ (2015) MicroRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress. Circ Res 116:1157–1169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chisalita SI, Arnqvist HJ (2004) Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol Endocrinol Metab 286:E896–E901

    Article  CAS  PubMed  Google Scholar 

  • Chisalita SI, Johansson GS, Liefvendahl E, Back K, Arnqvist HJ (2009) Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. J Mol Endocrinol 43:231–239

    Article  CAS  PubMed  Google Scholar 

  • Cittadini A, Stromer H, Vatner DE, Grossman JD, Katz SE, Clark R, Morgan JP, Douglas PS (1997) Consequences of growth hormone deficiency on cardiac structure, function, and beta-adrenergic pathway: studies in mutant dwarf rats. Endocrinology 138:5161–5169

    CAS  PubMed  Google Scholar 

  • Colao A, Di Somma C, Filippella M, Rota F, Pivonello R, Orio F, Vitale G, Lombardi G (2004) Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency. Clin Endocrinol 61:360–366

    Article  CAS  Google Scholar 

  • Csiszar A, Gautam T, Sosnowska D, Tarantini S, Banki E, Tucsek Z, Toth P, Losonczy G, Koller A, Reglodi D, Giles CB, Wren JD, Sonntag WE, Ungvari Z (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307:H292–H306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Csiszar A, Labinskyy N, Orosz Z, Xiangmin Z, Buffenstein R, Ungvari Z (2007) Vascular aging in the longest-living rodent, the naked mole-rat. Am J Phys 293:H919–H927

    CAS  Google Scholar 

  • Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z (2008) Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295:H1882–H1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Csiszar A, Tucsek Z, Toth P, Sosnowska D, Gautam T, Koller A, Deak F, Sonntag WE and Ungvari ZI (2013) Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in beta-amyloid generation and AD. Am J Physiol Heart Circ Physiol

  • D’Costa AP, Ingram RL, Lenham JE, Sonntag WE (1993) The regulation and mechanisms of action of growth hormone and insulin-like growth factor 1 during normal ageing. J Reprod Fertil Suppl 46:87–98

    PubMed  Google Scholar 

  • Daniel JM, Penzkofer D, Teske R, Dutzmann J, Koch A, Bielenberg W, Bonauer A, Boon RA, Fischer A, Bauersachs J, van Rooij E, Dimmeler S, Sedding DG (2014) Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury. Cardiovasc Res 103:564–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deak F, Sonntag WE (2012) Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1. J Gerontol A Biol Sci Med Sci 67:611–625

    Article  PubMed  CAS  Google Scholar 

  • Demirci B, Demir O, Dost T, Birincioglu M (2014) Antioxidative effect of aspirin on vascular function of aged ovariectomized rats. Age (Dordr) 36:223–229

    Article  CAS  Google Scholar 

  • Doebele C, Bonauer A, Fischer A, Scholz A, Reiss Y, Urbich C, Hofmann WK, Zeiher AM, and Dimmeler S Members of the microRNA-17-92 cluster exhibit a cell intrinsic anti-angiogenic function in endothelial cells. Blood 115(23):4944–4950

  • Donato AJ, Lesniewski LA, Stuart D, Walker AE, Henson G, Sorensen L, Li D, Kohan DE (2014) Smooth muscle specific disruption of the endothelin-a receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development. Life Sci 118:238–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dozmorov MG, Giles CB, Wren JD (2011) Predicting gene ontology from a global meta-analysis of 1-color microarray experiments. BMC Bioinformatics 12(Suppl 10):S14

    Article  PubMed  PubMed Central  Google Scholar 

  • Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179–183

    Article  CAS  PubMed  Google Scholar 

  • Edouard T, Grunenwald S, Gennero I, Salles JP, Tauber M (2009) Prevalence of IGF1 deficiency in prepubertal children with isolated short stature. Eur J Endocrinol 161:43–50

    Article  CAS  PubMed  Google Scholar 

  • Ekenstedt KJ, Sonntag WE, Loeser RF, Lindgren BR, Carlson CS (2006) Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints. Arthritis Rheum 54:3850–3858

    Article  CAS  PubMed  Google Scholar 

  • Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ (2000) Early growth, adult income, and risk of stroke. Stroke 31:869–874

    Article  CAS  PubMed  Google Scholar 

  • Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ (1999) Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 318:427–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eriksson JG, Forsen TJ, Kajantie E, Osmond C, Barker DJ (2007) Childhood growth and hypertension in later life. Hypertension 49:1415–1421

    Article  CAS  PubMed  Google Scholar 

  • Fenn AM, Smith KM, Lovett-Racke AE, Guerau-de-Arellano M, Whitacre CC, Godbout JP (2013) Increased micro-RNA 29b in the aged brain correlates with the reduction of insulin-like growth factor-1 and fractalkine ligand. Neurobiol Aging 34:2748–2758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO (2008) Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 7:681–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forsdahl A (1978) Living conditions in childhood and subsequent development of risk factors for arteriosclerotic heart disease. The cardiovascular survey in Finnmark 1974-75. J Epidemiol Community Health 32:34–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franco L, Williams FM, Trofimov S, Malkin I, Surdulescu G, Spector T, Livshits G (2014) Assessment of age-related changes in heritability and IGF-1 gene effect on circulating IGF-1 levels. Age (Dordr) 36:9622

    Article  CAS  Google Scholar 

  • Fulop N, Feng W, Xing D, He K, Not LG, Brocks CA, Marchase RB, Miller AP, Chatham JC (2008) Aging leads to increased levels of protein O-linked N-acetylglucosamine in heart, aorta, brain and skeletal muscle in Brown-Norway rats. Biogerontology 9:139–151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gavazzi I, Boyle KS, Edgar D, Cowen T (1995) Reduced laminin immunoreactivity in the blood vessel wall of ageing rats correlates with reduced innervation in vivo and following transplantation. Cell Tissue Res 281:23–32

    Article  CAS  PubMed  Google Scholar 

  • Giedd JN, Clasen LS, Lenroot R, Greenstein D, Wallace GL, Ordaz S, Molloy EA, Blumenthal JD, Tossell JW, Stayer C, Samango-Sprouse CA, Shen D, Davatzikos C, Merke D, Chrousos GP (2006) Puberty-related influences on brain development. Mol Cell Endocrinol 254-255:154–162

    Article  CAS  PubMed  Google Scholar 

  • Gillman MW (2005) Developmental origins of health and disease. N Engl J Med 353:1848–1850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goddings AL, Mills KL, Clasen LS, Giedd JN, Viner RM, Blakemore SJ (2014) The influence of puberty on subcortical brain development. NeuroImage 88:242–251

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldbourt U, Tanne D (2002) Body height is associated with decreased long-term stroke but not coronary heart disease mortality? Stroke 33:743–748

    Article  PubMed  Google Scholar 

  • Gonzalez-Guardia L, Yubero-Serrano EM, Rangel-Zuniga O, Marin C, Camargo A, Perez-Martinez P, Delgado-Lista J, Gomez-Delgado F, Garcia-Rios A, Tinahones FJ, Roche HM, Perez-Jimenez F, Lopez-Miranda J (2014) Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study. Age (Dordr) 36:9681

    Article  CAS  Google Scholar 

  • Grabowska W, Kucharewicz K, Wnuk M, Lewinska A, Suszek M, Przybylska D, Mosieniak G, Sikora E, Bielak-Zmijewska A (2015) Curcumin induces senescence of primary human cells building the vasculature in a DNA damage and ATM-independent manner. Age (Dordr) 37:9744

    Article  CAS  Google Scholar 

  • Grillari J, Grillari-Voglauer R Novel modulators of senescence, aging, and longevity: small non-coding RNAs enter the stage. Exp Gerontol 45:302–311

  • Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3:70ra13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heiss C, Sansone R, Karimi H, Krabbe M, Schuler D, Rodriguez-Mateos A, Kraemer T, Cortese-Krott MM, Kuhnle GG, Spencer JP, Schroeter H, Merx MW, Kelm M (2015) Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial. Age (Dordr) 37:9794

    Article  CAS  Google Scholar 

  • Helms SA, Azhar G, Zuo C, Theus SA, Bartke A, Wei JY (2010) Smaller cardiac cell size and reduced extra-cellular collagen might be beneficial for hearts of Ames dwarf mice. Int J Biol Sci 6:475–490

    Article  PubMed  PubMed Central  Google Scholar 

  • Hergenreider E, Heydt S, Treguer K, Boettger T, Horrevoets AJ, Zeiher AM, Scheffer MP, Frangakis AS, Yin X, Mayr M, Braun T, Urbich C, Boon RA, Dimmeler S (2012) Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14:249–256

    Article  CAS  PubMed  Google Scholar 

  • Higashi Y, Sukhanov S, Anwar A, Shai SY, Delafontaine P (2012) Aging, atherosclerosis, and IGF-1. J Gerontol A Biol Sci Med Sci 67:626–639

    Article  PubMed  CAS  Google Scholar 

  • Higashi Y, Sukhanov S, Anwar A, Shai SY, Delafontaine P (2010) IGF-1, oxidative stress and atheroprotection. Trends Endocrinol Metab 21:245–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hill CM, Arum O, Boparai RK, Wang F, Fang Y, Sun LY, Masternak MM, Bartke A (2015) Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age. Age (Dordr) 37:9765

    Article  CAS  Google Scholar 

  • Hua Y, Zhang Y, Ren J (2012) IGF-1 deficiency resists cardiac hypertrophy and myocardial contractile dysfunction: role of microRNA-1 and microRNA-133a. J Cell Mol Med 16:83–95

    Article  CAS  PubMed  Google Scholar 

  • Ibanez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M (2006) Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell 5:235–246

    Article  CAS  PubMed  Google Scholar 

  • Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A (2003) Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 58:291–296

    Article  PubMed  Google Scholar 

  • Inukai S, de Lencastre A, Turner M, Slack F (2012) Novel microRNAs differentially expressed during aging in the mouse brain. PLoS One 7:e40028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inukai S and Slack F (2013) MicroRNAs and the Genetic Network in Aging. J Mol Biol 425(19):3601–3608

  • Ito T, Yagi S, Yamakuchi M (2010) MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun 398:735–740

    Article  CAS  PubMed  Google Scholar 

  • Johansson GS, Chisalita SI, Arnqvist HJ (2008) Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level. Mol Cell Endocrinol 296:58–63

    Article  CAS  PubMed  Google Scholar 

  • Kajantie E, Osmond C, Barker DJ, Forsen T, Phillips DI, Eriksson JG (2005) Size at birth as a predictor of mortality in adulthood: a follow-up of 350 000 person-years. Int J Epidemiol 34:655–663

    Article  PubMed  Google Scholar 

  • Kim CW, Kumar S, Son DJ, Jang IH, Griendling KK, Jo H (2014) Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice. Arterioscler Thromb Vasc Biol 34:1412–1421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JM, Jung KH, Chu K, Lee ST, Ban J, Moon J, Kim M, Lee SK, Roh JK (2015) Atherosclerosis-related circulating MicroRNAs as a predictor of stroke recurrence. Transl Stroke Res 6:191–197

    Article  CAS  PubMed  Google Scholar 

  • Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946

    Article  CAS  PubMed  Google Scholar 

  • Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42:D68–D73

    Article  CAS  PubMed  Google Scholar 

  • Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S (2007) Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 101:59–68

    Article  CAS  PubMed  Google Scholar 

  • Laron Z, Klinger B, Silbergeld A (1999) Patients with Laron syndrome have osteopenia/osteoporosis. J Bone Miner Res 14:156–157

    Article  CAS  PubMed  Google Scholar 

  • Lee S, Yu KR, Ryu YS, Oh YS, Hong IS, Kim HS, Lee JY, Kim S, Seo KW, Kang KS (2014) miR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18. Age (Dordr) 36:9724

    Article  PubMed Central  CAS  Google Scholar 

  • Leiser SF, Miller RA (2010) Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol 30:871–884

    Article  CAS  PubMed  Google Scholar 

  • Leung A, Trac C, Jin W, Lanting L, Akbany A, Saetrom P, Schones DE, Natarajan R (2013) Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circ Res 113:266–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li LJ, Huang Q, Zhang N, Wang GB, Liu YH (2014) miR-376b-5p regulates angiogenesis in cerebral ischemia. Mol Med Rep 10:527–535

    CAS  PubMed  Google Scholar 

  • Li Q, Wu S, Li SY, Lopez FL, Du M, Kajstura J, Anversa P, Ren J (2007) Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol 292:H1398–H1403

    Article  CAS  Google Scholar 

  • Liu D, Wang D, Xu Z, Gao J, Liu M, Liu Y, Jiang M, Zheng D (2015) Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage. Age (Dordr) 37:97

    Article  CAS  Google Scholar 

  • Longobardi S, Cittadini A, Stromer H, Katz SE, Grossman JD, Clark RG, Morgan JP, Douglas PS (2000) Echocardiographic assessment of cardiac morphology and function in mutant dwarf rats. Growth Hormon IGF Res 10:242–247

    Article  CAS  Google Scholar 

  • Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta N, Steer BM, Ingram AJ, Gupta M, Al-Omran M, Teoh H, Marsden PA, Verma S (2012) MicroRNA-145 targeted therapy reduces atherosclerosis. Circulation 126:S81–S90

    Article  CAS  PubMed  Google Scholar 

  • Low SK, Takahashi A, Cha PC, Zembutsu H, Kamatani N, Kubo M, Nakamura Y (2012) Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. Hum Mol Genet 21:2102–2110

    Article  CAS  PubMed  Google Scholar 

  • Loyer X, Potteaux S, Vion AC, Guerin CL, Boulkroun S, Rautou PE, Ramkhelawon B, Esposito B, Dalloz M, Paul JL, Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A (2014) Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ Res 114:434–443

    Article  CAS  PubMed  Google Scholar 

  • Maes OC, An J, Sarojini H, Wang E (2008) Murine microRNAs implicated in liver functions and aging process. Mech Ageing Dev 129:534–541

    Article  CAS  PubMed  Google Scholar 

  • Manz HJ, Vester J, Lavenstein B (1979) Dissecting aneurysm of cerebral arteries in childhood and adolescence. Case report and literature review of 20 cases. Virchows Arch A Pathol Anat Histol 384:325–335

    Article  CAS  PubMed  Google Scholar 

  • Marino G, Ugalde AP, Fernandez AF, Osorio FG, Fueyo A, Freije JM, Lopez-Otin C (2010) Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function. Proc Natl Acad Sci U S A 107:16268–16273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maynard SP, Miller RA (2006) Fibroblasts from long-lived Snell dwarf mice are resistant to oxygen-induced in vitro growth arrest. Aging Cell 5:89–96

    Article  CAS  PubMed  Google Scholar 

  • Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, Vasa-Nicotera M, Ippoliti A, Novelli G, Melino G, Lauro R, Federici M (2009) MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 120:1524–1532

    Article  CAS  PubMed  Google Scholar 

  • Mercken EM, Majounie E, Ding J, Guo R, Kim J, Bernier M, Mattison J, Cookson MR, Gorospe M, de Cabo R, Abdelmohsen K (2013) Age-associated miRNA alterations in skeletal muscle from rhesus monkeys reversed by caloric restriction. Aging (Albany NY) 5:692–703

    Article  CAS  Google Scholar 

  • Mourmoura E, Couturier K, Hininger-Favier I, Malpuech-Brugere C, Azarnoush K, Richardson M, Demaison L (2014) Functional changes of the coronary microvasculature with aging regarding glucose tolerance, energy metabolism, and oxidative stress. Age (Dordr) 36:9670

    Article  CAS  Google Scholar 

  • Murakami S, Salmon A, Miller RA (2003) Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J 17:1565–1566

    CAS  PubMed  Google Scholar 

  • Nieves-Martinez E, Sonntag WE, Wilson A, Donahue A, Molina DP, Brunso-Bechtold J, Nicolle MM (2010) Early-onset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation. J Endocrinol 204:31–36

    Article  CAS  PubMed  Google Scholar 

  • O’Rourke JR, Olson EN (2011) Modulating the MicroRNArchitecture of an aging aorta. Circ Res 109:1098–1099

    Article  PubMed  CAS  Google Scholar 

  • Ono K, Kuwabara Y, Han J (2011) MicroRNAs and cardiovascular diseases. FEBS J 278:1619–1633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osmond C, Kajantie E, Forsen TJ, Eriksson JG, Barker DJ (2007) Infant growth and stroke in adult life: the Helsinki birth cohort study. Stroke 38:264–270

    Article  PubMed  Google Scholar 

  • Page MM, Salmon AB, Leiser SF, Robb EL, Brown MF, Miller RA, Stuart JA (2009) Mechanisms of stress resistance in Snell dwarf mouse fibroblasts: enhanced antioxidant and DNA base excision repair capacity, but no differences in mitochondrial metabolism. Free Radic Biol Med 46:1109–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM (2010) Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J 24:1–7

    Article  CAS  Google Scholar 

  • Park TJ, Boyd K, Curran T (2006) Cardiovascular and craniofacial defects in Crk-null mice. Mol Cell Biol 26:6272–6282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parker DR, Lapane KL, Lasater TM, Carleton RA (1998) Short stature and cardiovascular disease among men and women from two southeastern New England communities. Int J Epidemiol 27:970–975

    Article  CAS  PubMed  Google Scholar 

  • Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peper JS, van den Heuvel MP, Mandl RC, Hulshoff Pol HE, van Honk J (2011) Sex steroids and connectivity in the human brain: a review of neuroimaging studies. Psychoneuroendocrinology 36:1101–1113

    Article  CAS  PubMed  Google Scholar 

  • Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24:177–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramsey MM, Ingram RL, Cashion AB, Ng AH, Cline JM, Parlow AF, Sonntag WE (2002) Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology 143:4139–4142

    Article  CAS  PubMed  Google Scholar 

  • Reddy AK, Hartley CJ, Pham TT, Darlington G, Entman ML, Taffet GE (2014) Young little mice express a premature cardiovascular aging phenotype. J Gerontol A Biol Sci Med Sci 69:152–159

    Article  CAS  PubMed  Google Scholar 

  • Reijerkerk A, Lopez-Ramirez MA, van Het Hof B, Drexhage JA, Kamphuis WW, Kooij G, Vos JB, van der Pouw Kraan TC, van Zonneveld AJ, Horrevoets AJ, Prat A, Romero IA, de Vries HE (2013) MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis. J Neurosci 33:6857–6863

    Article  CAS  PubMed  Google Scholar 

  • Rojanathammanee L, Rakoczy S, Kopchick J, Brown-Borg HM (2014) Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice. Age (Dordr) 36:9687

    Article  CAS  Google Scholar 

  • Rotllan N, Ramirez CM, Aryal B, Esau CC, Fernandez-Hernando C (2013) Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr−/− mice—brief report. Arterioscler Thromb Vasc Biol 33:1973–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutnam ZJ, Wight TN, Yang BB (2013) miRNAs regulate expression and function of extracellular matrix molecules. Matrix Biol 32:74–85

    Article  CAS  PubMed  Google Scholar 

  • Rutnam ZJ, Yang BB (2012) The non-coding 3′ UTR of CD44 induces metastasis by regulating extracellular matrix functions. J Cell Sci 125:2075–2085

    Article  CAS  PubMed  Google Scholar 

  • Sadagurski M, Landeryou T, Cady G, Kopchick JJ, List EO, Berryman DE, Bartke A, and Miller RA (2015) Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice. Aging Cell

  • Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA (2005) Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Phys Endocrinol Metab 289:E23–E29

    Article  CAS  Google Scholar 

  • Sathyan S, Koshy LV, Balan S, Easwer HV, Premkumar S, Nair S, Bhattacharya RN, Alapatt JP, Banerjee M (2014) Association of Versican (VCAN) gene polymorphisms rs251124 and rs2287926 (G428D), with intracranial aneurysm. Meta Gene 2:651–660

    Article  PubMed  PubMed Central  Google Scholar 

  • Sato F, Tsuchiya S, Meltzer SJ, Shimizu K (2011) MicroRNAs and epigenetics. FEBS J 278:1598–1609

    Article  CAS  PubMed  Google Scholar 

  • Satterthwaite TD, Shinohara RT, Wolf DH, Hopson RD, Elliott MA, Vandekar SN, Ruparel K, Calkins ME, Roalf DR, Gennatas ED, Jackson C, Erus G, Prabhakaran K, Davatzikos C, Detre JA, Hakonarson H, Gur RC, Gur RE (2014) Impact of puberty on the evolution of cerebral perfusion during adolescence. Proc Natl Acad Sci U S A 111:8643–8648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sen A, Most P, Peppel K (2014) Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction. FEBS Lett 588:906–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shai SY, Sukhanov S, Higashi Y, Vaughn C, Kelly J, Delafontaine P (2010) Smooth muscle cell-specific insulin-like growth factor-1 overexpression in Apoe−/− mice does not alter atherosclerotic plaque burden but increases features of plaque stability. Arterioscler Thromb Vasc Biol 30:1916–1924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Small TW, Bolender Z, Bueno C, O’Neil C, Nong Z, Rushlow W, Rajakumar N, Kandel C, Strong J, Madrenas J, Pickering JG (2006) Wilms’ tumor 1-associating protein regulates the proliferation of vascular smooth muscle cells. Circ Res 99:1338–1346

    Article  CAS  PubMed  Google Scholar 

  • Small TW, Penalva LO, Pickering JG (2007) Vascular biology and the sex of flies: regulation of vascular smooth muscle cell proliferation by wilms’ tumor 1-associating protein. Trends Cardiovasc Med 17:230–234

    Article  CAS  PubMed  Google Scholar 

  • Small TW, Pickering JG (2009) Nuclear degradation of Wilms tumor 1-associating protein and survivin splice variant switching underlie IGF-1-mediated survival. J Biol Chem 284:24684–24695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith-Vikos T, Slack FJ (2012) MicroRNAs and their roles in aging. J Cell Sci 125:7–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty S, Lee S, Bennett C, Ingram R, Moore T, Ramsey M (2005a) Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146:2920–2932

    Article  CAS  PubMed  Google Scholar 

  • Sonntag WE, Csiszar A (2012) deCabo R, Ferrucci L, and Ungvari Z. Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 67:587–598

    Article  PubMed  CAS  Google Scholar 

  • Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W, Ungvari Z (2013) Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5:27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R (2000) The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat 197(Pt 4):575–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett SA, Thornton PL, Khan AS (1999) Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol A Biol Sci Med Sci 54:B521–B538

    Article  CAS  PubMed  Google Scholar 

  • Sonntag WE, Ramsey M, Carter CS (2005b) Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res Rev 4:195–212

    Article  CAS  PubMed  Google Scholar 

  • Sorensen K, Aksglaede L, Petersen JH, Andersson AM, Juul A (2012) Serum IGF1 and insulin levels in girls with normal and precocious puberty. Eur J Endocrinol 166:903–910

    Article  PubMed  CAS  Google Scholar 

  • Stellos K, Dimmeler S (2014) Vascular microRNAs: from disease mechanisms to therapeutic targets. Circ Res 114:3–4

    Article  CAS  PubMed  Google Scholar 

  • Steuerman R, Shevah O, Laron Z (2011) Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol 164:485–489

    Article  CAS  PubMed  Google Scholar 

  • Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC (2007) Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 100:1164–1173

    Article  CAS  PubMed  Google Scholar 

  • Suarez Y, Fernandez-Hernando C, Yu J, Gerber SA, Harrison KD, Pober JS, Iruela-Arispe ML, Merkenschlager M, Sessa WC (2008) Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci U S A 105:14082–14087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sukhanov S, Higashi Y, Shai SY, Vaughn C, Mohler J, Li Y, Song YH, Titterington J, Delafontaine P (2007) IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 27:2684–2690

    Article  CAS  PubMed  Google Scholar 

  • Svensson D, Gidlof O, Turczynska KM, Erlinge D, Albinsson S, Nilsson BO (2014) Inhibition of microRNA-125a promotes human endothelial cell proliferation and viability through an antiapoptotic mechanism. J Vasc Res 51:239–245

    Article  CAS  PubMed  Google Scholar 

  • Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A and Ungvari Z (2015) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14(6):1034–1044

  • Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33:1732–1742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, Koller A, Sonntag WE, Csiszar A, and Ungvari Z (2014) IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab 34(12):1887–1897

  • Troncoso R, Vicencio JM, Parra V, Nemchenko A, Kawashima Y, Del Campo A, Toro B, Battiprolu PK, Aranguiz P, Chiong M, Yakar S, Gillette TG, Hill JA, Abel ED, Leroith D, Lavandero S (2012) Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy. Cardiovasc Res 93:320–329

    Article  CAS  PubMed  Google Scholar 

  • Tucsek Z, Toth P, Sosnowsk D, Gautam T, Mitschelen M, Koller A, Szalai G, Sonntag WE, Ungvari Z and Csiszar A (2013) Obesity in aging exacerbates blood brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease J Gerontol A Biol Med Sci 69(10):1212–1226

  • Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352

    Article  PubMed  PubMed Central  Google Scholar 

  • Ungvari Z, Csiszar A (2012) The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci 67:599–610

    Article  PubMed  CAS  Google Scholar 

  • Ungvari Z, Csiszar A, Huang A, Kaminski PM, Wolin MS, Koller A (2003) High pressure induces superoxide production in isolated arteries via protein kinase C-dependent activation of NAD(P)H oxidase. Circulation 108:1253–1258

    Article  CAS  PubMed  Google Scholar 

  • Ungvari Z, Gautam T, Koncz P, Henthorn JC, Pinto JT, Ballabh P, Yan H, Mitschelen M, Farley J, Sonntag WE, Csiszar A (2010) Vasoprotective effects of life span-extending Peripubertal GH replacement in Lewis dwarf rats. J Gerontol A Biol Sci Med Sci 65:1145–1156

    Article  PubMed  CAS  Google Scholar 

  • Ungvari Z, Sosnowska D, Podlutsky A, Koncz P, Sonntag WE, Csiszar A (2011) Free radical production, antioxidant capacity, and oxidative stress response signatures in fibroblasts from Lewis dwarf rats: effects of life span-extending peripubertal GH treatment. J Gerontol A Biol Sci Med Sci 66:501–510

    Article  PubMed  CAS  Google Scholar 

  • Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A, Csiszar A, Losonczy G, Valcarcel-Ares MN, Sonntag WE, Csiszar A (2013) Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68:877–891

    Article  CAS  PubMed  Google Scholar 

  • van Abeelen AF, Elias SG, Bossuyt PM, Grobbee DE, van der Schouw YT, Roseboom TJ, Uiterwaal CS (2012) Cardiovascular consequences of famine in the young. Eur Heart J 33:538–545

    Article  PubMed  Google Scholar 

  • Vasa-Nicotera M, Chen H, Tucci P, Yang AL, Saintigny G, Menghini R, Mahe C, Agostini M, Knight RA, Melino G, Federici M (2011) miR-146a is modulated in human endothelial cell with aging. Atherosclerosis 217:326–330

    Article  CAS  PubMed  Google Scholar 

  • Victoria B, Dhahbi JM, Nunez Lopez YO, Spinel L, Atamma H, Spindler SR and Masternak MM (2015) Circulating microRNA signature of genotype-by-age interactions in the long-lived Ames dwarf mouse. Aging Cell 14(6):1055–1066

  • Walker AE, Henson GD, Reihl KD, Nielson EI, Morgan RG, Lesniewski LA, Donato AJ (2014) Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries. Age (Dordr) 36:559–569

    Article  CAS  Google Scholar 

  • Wang M, Miller RA (2012) Fibroblasts from long-lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress. Aging Cell 11:668–674

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weber M, Kim S, Patterson N, Rooney K, Searles CD (2014) MiRNA-155 targets myosin light chain kinase and modulates actin cytoskeleton organization in endothelial cells. Am J Physiol Heart Circ Physiol 306:H1192–H1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wren JD (2009) A global meta-analysis of microarray expression data to predict unknown gene functions and estimate the literature-data divide. Bioinformatics 25:1694–1701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wren JD, Garner HR (2004) Shared relationship analysis: ranking set cohesion and commonalities within a literature-derived relationship network. Bioinformatics 20:191–198

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Xiao H, Laguna-Fernandez A, Villarreal G Jr, Wang KC, Geary GG, Zhang Y, Wang WC, Huang HD, Zhou J, Li YS, Chien S, Garcia-Cardena G, Shyy JY (2011) Flow-dependent regulation of Kruppel-like factor 2 is mediated by MicroRNA-92a. Circulation 124:633–641

    Article  CAS  PubMed  Google Scholar 

  • Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G (2005) Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem 280:9330–9335

    Article  CAS  PubMed  Google Scholar 

  • Yasuno K, Bakircioglu M, Low SK, Bilguvar K, Gaal E, Ruigrok YM, Niemela M, Hata A, Bijlenga P, Kasuya H, Jaaskelainen JE, Krex D, Auburger G, Simon M, Krischek B, Ozturk AK, Mane S, Rinkel GJ, Steinmetz H, Hernesniemi J, Schaller K, Zembutsu H, Inoue I, Palotie A, Cambien F, Nakamura Y, Lifton RP, Gunel M (2011) Common variant near the endothelin receptor type a (EDNRA) gene is associated with intracranial aneurysm risk. Proc Natl Acad Sci U S A 108:19707–19712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zampetaki A, Attia R, Mayr U, Gomes RS, Phinikaridou A, Yin X, Langley SR, Willeit P, Lu R, Fanshawe B, Fava M, Barallobre-Barreiro J, Molenaar C, So PW, Abbas A, Jahangiri M, Waltham M, Botnar R, Smith A, Mayr M (2014) Role of miR-195 in aortic aneurysmal disease. Circ Res 115:857–866

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Azhar G, Wei JY (2012) The expression of microRNA and microRNA clusters in the aging heart. PLoS One 7:e34688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu Y, Davis S, Stephens R, Meltzer PS, Chen Y (2008) GEOmetadb: powerful alternative search engine for the gene expression omnibus. Bioinformatics 24:2798–2800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, Rao P, Farinelli L, Delalle I, Schmitt A, Falkai P, Bahari-Javan S, Burkhardt S, Sananbenesi F, Fischer A (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the American Heart Association (ST, AC, MNVA, ZT and ZU), the Oklahoma Center for the Advancement of Science and Technology (to AC, ZU, WES), the Oklahoma IDeA Network for Biomedical Research Excellence (to AC), the NIH (AG031085 to AC; AT006526 to ZU; AG038747 and NS056218 to WES and AC; 5U54GM104938 to JW), the Ellison Medical Foundation (to WES), and the Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center (to JW and ZU; P30 AG028718).

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Authors and Affiliations

  1. Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Stefano Tarantini, Cory B. Giles, Jonathan D. Wren, Nicole M. Ashpole, M. Noa Valcarcel-Ares, William E. Sonntag, Zoltan Ungvari & Anna Csiszar

  2. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini, Zoltan Ungvari & Anna Csiszar

  3. Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, Oklahoma City, OK, USA

    Cory B. Giles & Jonathan D. Wren

  4. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    Cory B. Giles & Jonathan D. Wren

  5. 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

    Jeanne Y. Wei

  6. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    William E. Sonntag, Zoltan Ungvari & Anna Csiszar

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  1. Stefano Tarantini
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  2. Cory B. Giles
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  4. Nicole M. Ashpole
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  7. William E. Sonntag
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  9. Anna Csiszar
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Correspondence to Anna Csiszar.

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All procedures were approved by and followed the guidelines of the Institutional Animal Care and Use Committee of OUHSC in accordance with the ARRIVE guidelines.

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The authors declare that they have no conflict of interest.

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Stefano Tarantini and Cory B. Giles contributed equally to this work.

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Tarantini, S., Giles, C.B., Wren, J.D. et al. 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. AGE 38, 239–258 (2016). https://doi.org/10.1007/s11357-016-9943-9

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