DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Δ/− mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Δ/− mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/−. DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/− mice. Ercc1Δ/− mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.
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August 2017
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Human vascular smooth muscle cell derived from a skin precursor. Subjects with type-2 diabetes have fewer skin-derived precursors in their skin. Vascular smooth muscle cells derived from skin-derived precursors from subjects with type-2 diabetes carry persistent signatures of disease even weeks after being removed from the patient. Thus, skin-derived precursors may be a promising platform to study type-2 diabetes associated vascular disease in a dish. In Clinical Science volume 131, issue 15, Steinbach et al. describe new approach to studying human vascular smooth muscle cell (VSMC) pathophysiology by examining VSMCs differentiated from progenitors found in skin (see pages 1801-1814).
Research Article|
July 13 2017
Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/− mice
Haiyan Wu;
Haiyan Wu
*
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
2Department of Pharmacology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China
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Bibi S. van Thiel;
Bibi S. van Thiel
*
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
4Department of Vascular Surgery, Erasmus University Medical Center Rotterdam, The Netherlands
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Paula K. Bautista-Niño;
Paula K. Bautista-Niño
*
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
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Erwin Reiling;
Erwin Reiling
5Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Matej Durik;
Matej Durik
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
6Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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Frank P.J. Leijten;
Frank P.J. Leijten
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
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Yanto Ridwan;
Yanto Ridwan
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
7Department of Radiology and Nuclear Medicine, Erasmus University Medical Center Rotterdam, The Netherlands
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Renata M.C. Brandt;
Renata M.C. Brandt
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
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Harry van Steeg;
Harry van Steeg
5Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Martijn E.T. Dollé;
Martijn E.T. Dollé
5Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Wilbert P. Vermeij;
Wilbert P. Vermeij
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
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Jan H.J. Hoeijmakers;
Jan H.J. Hoeijmakers
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
8CECAD Forschungszentrum, Universität zu Köln, Germany
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Jeroen Essers;
Jeroen Essers
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
4Department of Vascular Surgery, Erasmus University Medical Center Rotterdam, The Netherlands
9Department of Radiation Oncology, Erasmus University Medical Center Rotterdam, The Netherlands
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Ingrid van der Pluijm;
Ingrid van der Pluijm
3Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
4Department of Vascular Surgery, Erasmus University Medical Center Rotterdam, The Netherlands
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A.H. Jan Danser;
A.H. Jan Danser
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
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Anton J.M. Roks
1Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands
Correspondence: A.J.M. Roks ([email protected])
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Publisher: Portland Press Ltd
Received:
January 11 2017
Revision Received:
June 07 2017
Accepted:
June 15 2017
Accepted Manuscript online:
June 15 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (15): 1941–1953.
Article history
Received:
January 11 2017
Revision Received:
June 07 2017
Accepted:
June 15 2017
Accepted Manuscript online:
June 15 2017
Citation
Haiyan Wu, Bibi S. van Thiel, Paula K. Bautista-Niño, Erwin Reiling, Matej Durik, Frank P.J. Leijten, Yanto Ridwan, Renata M.C. Brandt, Harry van Steeg, Martijn E.T. Dollé, Wilbert P. Vermeij, Jan H.J. Hoeijmakers, Jeroen Essers, Ingrid van der Pluijm, A.H. Jan Danser, Anton J.M. Roks; Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/− mice. Clin Sci (Lond) 1 August 2017; 131 (15): 1941–1953. doi: https://doi.org/10.1042/CS20170026
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