期刊
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
卷 68, 期 8, 页码 877-891出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/gls242
关键词
Angiogenesis; Capillary density; Vascular aging; Cerebrovascular; Cardiovascular aging; Epigenetics
资金
- American Federation for Aging Research
- Oklahoma Center for the Advancement of Science and Technology
- American Heart Association
- National Institutes of Health [AG031085, AT006526, AG038747, NS056218, P01 AG11370]
- Ellison Medical Foundation
- Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center
- Hungarian National Development Agency [TAMOP/SROP-4.2.1/b-10/2/KONV-2010-0012]
- Hungarian National Science Research Funds [OTKA K71591]
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 x 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.
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