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.
Highlights
Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide and has an enormous economic burden on healthcare systems [1]
We have demonstrated that Ercc1 knockout in vascular endothelial cells (EC-KO) selectively affects endothelium-derived nitric oxide (NO) and leads to decreased end-organ perfusion, vascular leakage, and increased wall thickness [7]
To address the question if a local vascular smooth muscle cells (VSMC) DNA repair defect is critical for the specific changes in vascular function as observed in Ercc1Δ/- mice, we investigated cardiovascular function in a mouse model with specific loss of Ercc1 function in smooth muscle cells (SMCs)
Summary
Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide and has an enormous economic burden on healthcare systems [1]. Several genetically modified mouse strains have been generated that model accelerated ageing These are based on a specific deficiency in DNA repair. Ercc1Δ/- mice display segmental progeria [18], which suggests that affected organs could be influenced by a local DNA damage process rather than a systemic one. There is a rapid development of carotid artery stiffness in Ercc1Δ/- mice which is absent in EC-KO [17] These differences suggest that some of the ageing features in the Ercc1Δ/- mice can be induced by DNA damage in VSMC [7, 17]. To address the question if a local VSMC DNA repair defect is critical for the specific changes in vascular function as observed in Ercc1Δ/- mice, we investigated cardiovascular function in a mouse model with specific loss of Ercc function in smooth muscle cells (SMCs). We focused on changes of NO-cGMP responsiveness since this is a major hallmark of ageing and DNA damage-related vascular dysfunction
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