Endothelial-to-mesenchymal transition (EndMT) is a pathophysiological change in the vascular endothelium commonly seen in the cardiovascular system. Elevated serum Growth differiention factor 15 (GDF15) has been reported in VTE patients, but the relationship and mechanism between GDF15, EndMT and VTE are still unclear. We performed a retrospective clinical study, and human serum GDF15 expression levels were detected. The mouse DVT model was established through subtotal ligation of the mouse inferior vena cava, and then we detected intimal changes and thrombi in the stenotic inferior vena cava by haematoxylin-eosin (HE) staining, Masson staining, and Sirius Red staining. The expression levels of GDF15 and SM22 were detected by immunohistochemistry and RT‒qPCR. Serum samples of mice were collected, and the expression level of GDF15 in serum was detected. Human umbilical vein endothelial cells (HUVECs) were stimulated with a cytokine mixture (TGF-β1 + TNF-α + IL-1β). The role and mechanism of GDF15 in EndMT and VTE were detected in HUVECs and in a DVT mice model. We found that serum GDF15 levels in both VTE patients and mouse DVT models were higher than those in the control group. EndMT was increased in the stenotic vascular tissue of mice. Further experiments showed that GDF15 could promote the EndMT of HUVECs and reduce their anticoagulation and antifibrinolytic ability through the smad2/p-smad2/snail pathway. Inhibition of mature GDF15 release can significantly reduce venous thrombotic fibre deposition in mice. GDF15 positively promotes EndMT through activation of the Smad2/psmad2/snail pathway, and inhibition of GDF15 expression can alleviate the EndMT process, further improving the coagulation and fibrinolytic function of endothelial cells and thus reducing the local fibre deposition of venous thrombi.

中文翻译：

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GDF15通过smad2/p-smad2通路促进EndMT影响静脉血栓形成

内皮间质转化（EndMT）是心血管系统中常见的血管内皮的病理生理变化。VTE患者血清生长分化因子15（GDF15）升高已有报道，但GDF15、EndMT和VTE之间的关系和机制仍不清楚。我们进行了回顾性临床研究，检测了人血清GDF15的表达水平。通过小鼠下腔静脉次全结扎建立小鼠DVT模型，通过苏木精-伊红（HE）染色、马森染色、天狼星红染色检测狭窄下腔静脉内膜变化和血栓情况。通过免疫组化和RT-qPCR检测GDF15和SM22的表达水平。采集小鼠血清样本，检测血清中GDF15的表达水平。用细胞因子混合物（TGF-β1 + TNF-α + IL-1β）刺激人脐静脉内皮细胞 (HUVEC)。在 HUVEC 和 DVT 小鼠模型中检测到 GDF15 在 EndMT 和 VTE 中的作用和机制。我们发现VTE患者和小鼠DVT模型的血清GDF15水平均高于对照组。小鼠狭窄血管组织中的 EndMT 增加。进一步实验表明，GDF15可以通过smad2/p-smad2/snail途径促进HUVECs的EndMT，降低其抗凝和抗纤溶能力。抑制成熟GDF15释放可显着减少小鼠静脉血栓纤维沉积。GDF15通过激活Smad2/psmad2/snail通路正向促进EndMT，抑制GDF15的表达可以缓解EndMT过程，进一步改善内皮细胞的凝血和纤溶功能，从而减少静脉血栓的局部纤维沉积。