Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands.
Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus MC, Rotterdam, Netherlands.
Oxid Med Cell Longev. 2021 Aug 31;2021:2308317. doi: 10.1155/2021/2308317. eCollection 2021.
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 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: SM22Cre+ fl/-). Vascular ageing features in SMC-KO and their wild-type littermates (WT: SM22Cre+ fl/+) 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.
持续未修复的 DNA 损伤已被确定为血管老化的一个致病因素。我们之前已经表明，在小鼠中，DNA 修复内切酶 ERCC1（切除修复交叉互补 1）的功能或表达缺陷会导致血管系统从出生后 8 周开始加速、非动脉粥样硬化性老化。内皮细胞特异性 ERCC1 敲除小鼠部分解释了这种老化，如内皮细胞特异性 ERCC1 敲除小鼠所示。在这项研究中，我们通过在小鼠中进行血管平滑肌细胞（SMC）特异性遗传去除 ERCC1 修复（SMC-KO：SM22Cre+ fl/-）来确定由于 DNA 损伤引起的血管老化。在 14 周和 25 周时检查 SMC-KO 和其野生型同窝仔鼠（WT：SM22Cre+ fl/+）的血管老化特征。与 WT 相比，SMC-KO 显示出心率、分数缩短和心输出量降低。与 WT 相比，SMC-KO 随着年龄从 14 周增加到 25 周，表现出进行性的非动脉粥样硬化性血管老化特征。观察到皮下微血管扩张减少和颈动脉僵硬增加。在器官浴中的主动脉环中测量的血管舒张反应显示出内皮依赖性和非内皮依赖性反应的减少，这主要是由于 NO-cGMP 信号转导减少。NADPH 氧化酶 2 和磷酸二酯酶 1 抑制改善了扩张。SMC-KO 小鼠显示出各种细胞因子水平升高，表明促炎和抗炎途径之间的平衡发生转移。总之，SMC-KO 小鼠在抗性和导管动脉中表现出进行性血管老化表型，与心脏重构和收缩功能障碍有关。由 DNA 损伤引起的变化可能仅限于 VSMC，但最终会影响 EC 介导的反应。NADPH 氧化酶 2 以及磷酸二酯酶 1 抑制恢复血管舒张表明，NO 生物利用度和 cGMP 降解减少在 DNA 损伤诱导的局部血管平滑肌细胞老化中均起作用。
