Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Nat Commun. 2022 Jul 25;13(1):4170. doi: 10.1038/s41467-022-31890-4.
Vascular dysfunction is a hallmark of chronic diseases in elderly. The contribution of the vasculature to lung repair and fibrosis is not fully understood. Here, we performed an epigenetic and transcriptional analysis of lung endothelial cells (ECs) from young and aged mice during the resolution or progression of bleomycin-induced lung fibrosis. We identified the transcription factor ETS-related gene (ERG) as putative orchestrator of lung capillary homeostasis and repair, and whose function is dysregulated in aging. ERG dysregulation is associated with reduced chromatin accessibility and maladaptive transcriptional responses to injury. Loss of endothelial ERG enhances paracrine fibroblast activation in vitro, and impairs lung fibrosis resolution in young mice in vivo. scRNA-seq of ERG deficient mouse lungs reveales transcriptional and fibrogenic abnormalities resembling those associated with aging and human lung fibrosis, including reduced number of general capillary (gCap) ECs. Our findings demonstrate that lung endothelial chromatin remodeling deteriorates with aging leading to abnormal transcription, vascular dysrepair, and persistent fibrosis following injury.
血管功能障碍是老年慢性疾病的一个标志。血管系统对肺修复和纤维化的贡献还不完全清楚。在这里，我们对年轻和老年小鼠在博来霉素诱导的肺纤维化消退或进展过程中肺内皮细胞（EC）进行了表观遗传学和转录组学分析。我们确定了转录因子 ETS 相关基因（ERG）是肺毛细血管稳态和修复的假定协调因子，其功能在衰老过程中失调。ERG 失调与染色质可及性降低以及对损伤的适应性转录反应不良有关。内皮细胞 ERG 的缺失会增强体外旁分泌成纤维细胞的激活，并损害年轻小鼠体内肺纤维化的消退。ERG 缺陷小鼠肺的 scRNA-seq 揭示了类似于与衰老和人类肺纤维化相关的转录和纤维发生异常，包括一般毛细血管（gCap）EC 的数量减少。我们的研究结果表明，随着年龄的增长，肺内皮细胞染色质重塑恶化，导致损伤后异常转录、血管修复不良和持续纤维化。
