DNA REPAIR DEFECT IN SMOOTH MUSCLE CELL REPRODUCES FEATURES OF AGE-RELATED VASCULAR DISEASE IN MICE. (April 2021)

• Record Type: Journal Article
• Authors: Ataabadi, Ehsan Ataei; Golshiri, Keivan; De Vries, René; Snyder, Gretchen L.; Zhang, Lei; Li, Peng; Davis, Robert E.; Jan Danser, A.H.; Roks, Anton J.M.
• Is Part Of: Journal of hypertension. Volume 39(2021)e-Supplement 1
• Publication Date: 2021-04
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000745072.54156.33
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: DNA damage and repair responses have been implicated in age-related vascular disease. Evidence in mice shows that deletion of the Ercc1 gene, encoding an endonuclease that participates in several DNA repair systems, leads to features of accelerated ageing. It is not known from which cell type the vascular aging effect of Ercc1 deletion originates. A possibility is local DNA damage in vascular smooth muscle cells (VSMC). We determined features of vascular aging in a mouse model with specific Ercc1 deletion in smooth muscle cells (SMC-KO). Design and method: 12 SMC-KO and 13 Wild-type (WT) littermates were generated using alpha SM22-Cre driven cre-lox deletion of Ercc1. Blood pressure (BP) and in vivo vasodilation (reactive hyperemia: RH) were measured at the age of 22 and 23 weeks respectively. Mice were sacrificed at 24 weeks. Thoracic aorta and iliac artery endothelium-dependent (ED) and –independent (EI) relaxation were assessed (wire myograph). Results: There was no significant difference in BP between WT and SMC-KO. RH was decreased in SMC-KO vs. WT by 73% (P = 0.008). In SMC-KO mice maximal relaxation in iliac arteries to acetylcholine (ED) and sodium nitroprusside donor (EI) were decreased as compared to WT (ED: 48.04 ± 6.80 vs. 86.16 ± 3.68, P = 0.001; EI: 79.84 ± 4.04 vs. 93.78 ± 2.13, P = 0.022). In aorta similar observations were made (ED: 17.11 ± 2.29 vs. 73.42 ± 4.29, P = 0.0001; EI 55.87 ± 4.77 vs. 69.01 ± 5.17, p = 0.007). When added in the organ bath ITI-214 acutely increased aortic EI relaxation both in WT (from 69.01 ± 5.17 to 80.53 ± 2.05, P = 0.006) and SMC-KO (from 55.87 ± 4.77 to 67.17 ± 3.70, P = 0.084). Conclusions: Local DNA damage in SMC causes a decrease of vasodilator responses. This effect is blood pressure-independent. Given that responses to sodium nitroprusside, a nitric oxide (NO) donor, and PDE1, a cGMP-metabolising enzyme, were both involved, most probably a decline of NO-cGMP signalling is involved.