Fibrosis is a pathological process characterized by abnormal activation of fibroblasts with increased synthesis of extracellular matrix components, including collagens. It may lead to loss of proper tissue architecture and organ function in clinical diseases such as systemic sclerosis and liver fibrosis. Excess accumulation of collagens is considered the primary indicator of fibrosis. Notch signaling has been reported to be involved in the fibrosis of many different organs, including the liver. Our previous study showed that the uterine-specific over-activation of canonical Notch1 signaling in the mouse uterus (Pgr^cre/+ Rosa26^N1ICD/+, OEx) results in complete infertility as a consequence of multiple developmental and physiological defects, together with increased collagen accumulation evidenced by Masson's staining. In this study, we further detected expressions of all 44 collagen genes in these Notch1 gain-of-function transgenic mice and found that 18 collagens have been largely affected. In another aspect, using an intrauterine adhesion model (IUA), we mimicked fibrosis in the mouse uterine. The results suggested that Notch receptors were upregulated only 3 days after induction, and most of the fibril-forming collagen began to upregulate 6 days after the surgery. Furthermore, when induced IUA in the N1ICD-OEx mice, the expression of collagens and fibrosis levels were significantly enhanced. At last, as a Notch signaling inhibitor, the γ-secretase inhibitor N-[N-(3,5-difl uorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) pretreatment could alleviate the expression of collagens and the symptoms of fibrosis. These results demonstrate that Notch signaling may play a role in upregulating collagens expression in endometrial fibrosis and might be a potential target of fibrosis therapy in the endometrium.

中文翻译：

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Notch1信号增强小鼠子宫胶原蛋白表达和纤维化

纤维化是一种病理过程，其特征是成纤维细胞异常活化，细胞外基质成分（包括胶原蛋白）的合成增加。它可能导致系统性硬化症和肝纤维化等临床疾病中适当的组织结构和器官功能丧失。胶原蛋白的过量积累被认为是纤维化的主要指标。据报道，Notch 信号与许多不同器官的纤维化有关，包括肝脏。我们之前的研究表明，小鼠子宫中典型 Notch1 信号的子宫特异性过度激活 ( Pgr ^cre/+ Rosa26 ^N1ICD/+, OEx) 导致完全不育，这是由于多种发育和生理缺陷，以及由 Masson 染色证明的胶原蛋白积累增加。在这项研究中，我们进一步检测了这些 Notch1 功能获得性转基因小鼠中所有 44 种胶原蛋白基因的表达，发现 18 种胶原蛋白受到了很大影响。在另一个方面，我们使用宫内粘连模型 (IUA)，模拟了小鼠子宫中的纤维化。结果表明，Notch 受体仅在诱导后 3 天上调，大部分原纤维形成胶原蛋白在手术后 6 天开始上调。此外，当在 N1ICD-OEx 小鼠中诱导 IUA 时，胶原蛋白的表达和纤维化水平显着增强。最后，作为 Notch 信号抑制剂，γ-分泌酶抑制剂 N-[N-(3, 5-二氟苯乙酰）-L-丙氨酰]-S-苯基甘氨酸叔丁酯（DAPT）预处理可以减轻胶原蛋白的表达和纤维化症状。这些结果表明，Notch 信号可能在上调子宫内膜纤维化中的胶原蛋白表达中发挥作用，并且可能是子宫内膜纤维化治疗的潜在靶点。