Vascular Ageing Features Caused by Selective DNA Damage in Smooth Muscle Cell.

Content Provider	Europe PMC
Author	Ataei Ataabadi, Ehsan Golshiri, Keivan van der Linden, Janette de Boer, Martine Duncker, Dirk J. Jüttner, Annika de Vries, René Van Veghel, Richard van der Pluijm, Ingrid Dutheil, Sophie Chalgeri, Suman Zhang, Lei Lin, Amy Davis, Robert E. Snyder, Gretchen L. Danser, A. H. Jan Roks, Anton J. M.
Copyright Year	2021
Abstract	Persistently unrepaired DNA damage has been identified as a causative factor for vascular ageing. We have previously shown that a defect in the function or expression of the DNA repair endonuclease ERCC1 (excision repair cross complement 1) in mice leads to accelerated, nonatherosclerotic ageing of the vascular system from as early as 8 weeks after birth. Removal of ERCC1 from endothelial alone partly explains this ageing, as shown in endothelial-specific Ercc1 knockout mice. In this study, we determined vascular ageing due to DNA damage in vascular smooth muscle cells, as achieved by smooth muscle-selective genetic removal of ERCC1 DNA repair in mice (SMC-KO: SM22αCre+ Ercc1fl/-). Vascular ageing features in SMC-KO and their wild-type littermates (WT: SM22αCre+ Ercc1fl/+) were examined at the age of 14 weeks and 25 weeks. Both SMC-KO and WT mice were normotensive. Compared to WT, SMC-KO showed a reduced heart rate, fractional shortening, and cardiac output. SMC-KO showed progressive features of nonatherosclerotic vascular ageing as they aged from 14 to 25 weeks. Decreased subcutaneous microvascular dilatation and increased carotid artery stiffness were observed. Vasodilator responses measured in aortic rings in organ baths showed decreased endothelium-dependent and endothelium-independent responses, mostly due to decreased NO-cGMP signaling. NADPH oxidase 2 and phosphodiesterase 1 inhibition improved dilations. SMC-KO mice showed elevated levels of various cytokines that indicate a balance shift in pro- and anti-inflammatory pathways. In conclusion, SMC-KO mice showed a progressive vascular ageing phenotype in resistant and conduit arteries that is associated with cardiac remodeling and contractile dysfunction. The changes induced by DNA damage might be limited to VSMC but eventually affect EC-mediated responses. The fact that NADPH oxidase 2 as wells as phosphodiesterase 1 inhibition restores vasodilation suggests that both decreased NO bioavailability and cGMP degradation play a role in local vascular smooth muscle cell ageing induced by DNA damage.
ISSN	19420900
Journal	Oxidative Medicine and Cellular Longevity
Volume Number	2021
PubMed Central reference number	PMC8423575
PubMed reference number	34504640
e-ISSN	19420994
DOI	10.1155/2021/2308317
Language	English
Publisher	Hindawi
Publisher Date	2021-08-31
Access Restriction	Open
Rights License	This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2021 Ehsan Ataei Ataabadi et al.
Content Type	Text
Resource Type	Article
Subject	Cell Biology Aging Medicine Biochemistry