title: Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells.
abstract: Age-related impairment of angiogenesis is likely to play a central role in cerebromicrovascular rarefaction and development of vascular cognitive impairment, but the underlying mechanisms remain elusive. To test the hypothesis that dysregulation of Dicer1 (ribonuclease III, a key enzyme of the microRNA [miRNA] machinery) impairs endothelial angiogenic capacity in aging, primary cerebromicrovascular endothelial cells (CMVECs) were isolated from young (3 months old) and aged (24 months old) Fischer 344 × Brown Norway rats. We found an age-related downregulation of Dicer1 expression both in CMVECs and in small cerebral vessels isolated from aged rats. In aged CMVECs, Dicer1 expression was increased by treatment with polyethylene glycol-catalase. Compared with young cells, aged CMVECs exhibited altered miRNA expression profile, which was associated with impaired proliferation, adhesion to vitronectin, collagen and fibronectin, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology), and impaired ability to form capillary-like structures. Overexpression of Dicer1 in aged CMVECs partially restored miRNA expression profile and significantly improved angiogenic processes. In young CMVECs, downregulation of Dicer1 (siRNA) resulted in altered miRNA expression profile associated with impaired proliferation, adhesion, migration, and tube formation, mimicking the aging phenotype. Collectively, we found that Dicer1 is essential for normal endothelial angiogenic processes, suggesting that age-related dysregulation of Dicer1-dependent miRNA expression may be a potential mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging.
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma HSC, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK 73104, USA. zoltan-ungvari@ouhsc.edu
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.forename: Andrej
authors.initials: A
authors.lastname: Podlutsky
authors.forename: Agnes
authors.initials: A
authors.lastname: Csiszar
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Losonczy
authors.forename: M Noa
authors.initials: MN
authors.lastname: Valcarcel-Ares
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology / Q000502:physiology; D000818:Animals; D001921:Brain / Q000098:blood supply*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D018384:Oxidative Stress; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D017382:Reactive Oxygen Species; C583537:Dicer1 protein, rat; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases