Bautista-Nino, Paula K., Portilla-Fernandez, Eliana, Rubio-Beltran, Eloisa, van der Linden, Janette J., de Vries, Rene, van Veghel, Richard, de Boer, Martine, Durik, Matej, Ridwan, Yanto, Brandt, Renata, Essers, Jeroen, Menzies, Robert, I, Thomas, Rachel, de Bruin, Alain, Duncker, Dirk J., van Beusekom, Heleen M. M., Ghanbari, Mohsen ORCID: 0000-0002-9476-7143, Hoeijmakers, Jan H. J., Sedlacek, Radislav, Touyz, Rhian M., Montezano, Augusto C., van der Pluijm, Ingrid, Danser, A. H. Jan, Haanes, Kristian A. and Roks, Anton J. M. (2020). Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction. Clin. Sci., 134 (7). S. 727 - 747. LONDON: PORTLAND PRESS LTD. ISSN 1470-8736

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Abstract

We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (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 with wild-type (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 with 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 (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BR In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bautista-Nino, Paula K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Portilla-Fernandez, ElianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rubio-Beltran, EloisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Linden, Janette J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Vries, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Veghel, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Boer, MartineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durik, MatejUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ridwan, YantoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandt, RenataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Essers, JeroenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menzies, Robert, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, RachelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Bruin, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duncker, Dirk J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Beusekom, Heleen M. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghanbari, MohsenUNSPECIFIEDorcid.org/0000-0002-9476-7143UNSPECIFIED
Hoeijmakers, Jan H. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sedlacek, RadislavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Touyz, Rhian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montezano, Augusto C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Pluijm, IngridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danser, A. H. JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haanes, Kristian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roks, Anton J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-338684
DOI: 10.1042/CS20190124
Journal or Publication Title: Clin. Sci.
Volume: 134
Number: 7
Page Range: S. 727 - 747
Date: 2020
Publisher: PORTLAND PRESS LTD
Place of Publication: LONDON
ISSN: 1470-8736
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRACING REVEALS; LINEAGE; DAMAGE; STRESS; MOUSE; HYPERPOLARIZATION; ACTIVATION; MECHANISM; CANCER; MICEMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33868

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