Local endothelial DNA repair defect causes aging-resembling endothelial-specific dysfunction

Bautista-Niño, P. K. et al. (2020) Local endothelial DNA repair defect causes aging-resembling endothelial-specific dysfunction. Clinical Science, 134(7), pp. 727-746. (doi: 10.1042/cs20190124) (PMID:32202295)

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Abstract

We previously identified genomic instability as a causative factor for vascular aging. In the present study determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 DNA repair in mice (EC-KO mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared to WT. EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared to WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide were intact. EC-KO showed increased superoxide production compared to WT, as measured in lung tissue, rich in endothelial cells. Arterial systolic blood pressure was increased at 3 months, but normal at 5 months, at which age cardiac output was decreased. Since no further signs of cardiac dysfunction were detected this decrease might be an adaptation to prevent an increase of blood pressure. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived nitric oxide. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.

Item Type:Articles
Additional Information:This study was supported by grants from the Netherlands CardioVascular Research Initiative: 706 an initiative with support of the Dutch Heart Foundation [CVON2011-11 (ARENA) and 707 CVON2014-11 (RECONNECT)]. Paula K. Bautista-Niño was financially supported by 708 Colciencias Colombia, a grant under Call 617 of 2013. AJMR and JJvdL are supported by 709 Dutch Heart Foundation grant # 2015T094, TKI-LSH grant EMCLSH19013, Stichting Lijf en 710 Leven, and a Human Disease Model Award from Erasmus MC. RMT is funded through a 711 British Herat Foundation Chair award (CH/12/4/29762). KAH was funded by a grant from the 712 International Headache Society. RS is supported by following grants: LM2015040 (Czech 713 Centre for Phenogenomics), Youth and Sports (MEYS) and by Academy of Sciences of the 714 Czech Republic (RVO 68378050). R.I.M. is funded by British Heart Foundation Fellowship 715 (BHF) FS/15/60/31510. JHJH is supported by the National Institute of Health (NIH)/National 716 Institute of Ageing (NIA) (PO1 AG017242), European Research Council Advanced Grants 717 DamAge and Dam2Age and Proof of Concept Grant Dementia, SFB628, Memorabel 718 (ZonMW), BBoL (NWO-ENW), and ONCODE Supported by the Dutch Cancer Society.
Keywords:General medicine.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Touyz, Professor Rhian
Authors: Bautista-Niño, P. K., Portilla-Fernandez, E., Rubio-Beltrán, E., van der Linden, J. J., de Vries, R., van Veghel, R., de Boer, M., Durik, M., Ridwan, Y., Brandt, R. M.C., Essers, J., Menzies, R. I., Thomas, R., de Bruin, A., Duncker, D. J., van Beusekom, H. M.M., Ghanbari, M., Hoeijmakers, J. H.J., Sedlacek, R., Touyz, R. M., Montezano, A. C., van der Pluijm, I., Danser, A.H. J., Haanes, K. A., and Roks, A. J.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Clinical Science
Publisher:Portland Press
ISSN:0143-5221
ISSN (Online):1470-8736
Published Online:23 March 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Clinical Science 134(7): 727-746
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190615Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762Institute of Cardiovascular & Medical Sciences