Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet and nitric oxide synthase inhibition, pulmonary fibrosis induced by bleomycin treatment, and liver fibrosis due to a choline-deficient diet. We also observed up-regulation of endothelial SOX9 in cardiac tissue from patients with heart failure. To test whether SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell–specific overexpression of Sox9, which promoted fibrosis in multiple organs and resulted in signs of heart failure. Endothelial Sox9 deletion prevented fibrosis and organ dysfunction in the two mouse models of heart failure as well as in the lung and liver fibrosis mouse models. Bulk and single-cell RNA sequencing of mouse endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory gene expression, leading to matrix deposition by endothelial cells. Moreover, mouse endothelial cells activated neighboring fibroblasts that then migrated and deposited matrix in response to SOX9, a process partly mediated by the secreted growth factor CCN2, a direct SOX9 target; endothelial cell–specific Sox9 deletion reversed these changes. These findings suggest a role for endothelial SOX9 as a fibrosis-promoting factor in different mouse organs during disease and imply that endothelial cells are an important regulator of fibrosis.

中文翻译：

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内皮细胞通过诱导转录因子 SOX9 的表达来驱动小鼠器官纤维化

纤维化是慢性疾病的标志。尽管成纤维细胞参与其中，但尚不清楚内皮细胞在多大程度上也能发挥作用。我们在几种不同的小鼠纤维化模型中检测到内皮细胞中转录因子Sox9的表达增加。这些模型包括压力超负荷引起的收缩性心力衰竭、高脂肪饮食和一氧化氮合酶抑制引起的舒张性心力衰竭、博来霉素治疗引起的肺纤维化以及缺乏胆碱饮食引起的肝纤维化。我们还观察到心力衰竭患者心脏组织中内皮 SOX9 的上调。为了测试 SOX9 诱导是否足以引起疾病，我们培育了内皮细胞特异性过度表达Sox9的小鼠，这会促进多个器官的纤维化并导致心力衰竭的迹象。在两种心力衰竭小鼠模型以及肺和肝纤维化小鼠模型中，内皮Sox9缺失可预防纤维化和器官功能障碍。对跨多个血管床的小鼠内皮细胞进行批量和单细胞 RNA 测序表明，SOX9 诱导细胞外基质、生长因子和炎症基因表达，导致内皮细胞沉积基质。此外，小鼠内皮细胞激活邻近的成纤维细胞，然后这些成纤维细胞响应 SOX9 迁移并沉积基质，这一过程部分由分泌性生长因子 CCN2（SOX9 的直接靶标）介导。内皮细胞特异性Sox9缺失逆转了这些变化。这些发现表明内皮 SOX9 在疾病期间的不同小鼠器官中作为纤维化促进因子发挥作用，并暗示内皮细胞是纤维化的重要调节因子。