Reciprocal enhancement of thrombosis by endothelial-to-mesenchymal transition induced by iliac vein compression
Reciprocal enhancement of thrombosis by endothelial-to-mesenchymal transition induced by iliac vein compression
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DOI：
10.1016/j.lfs.2019.116659
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发表时间：
2019-09-15
期刊：
影响因子：
6.1
通讯作者：
Li, Xiaoqiang
中科院分区：
文献类型：
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作者：
Hong, Lei;Du, Xiaolong;Li, Xiaoqiang
目的：内皮细胞间质转化（EndMT）是心血管系统中常见的血管内皮细胞的病理生理变化。髂静脉压迫综合征（IVCS）通常与内膜增生和血栓形成有关。然而，EndMT是否存在于IVCS中尚未报道。本研究旨在探讨EndMT与IVCS血栓形成的关系。主要方法：采用猪和小鼠IVCS模型，采用免疫荧光染色法检测狭窄髂静脉内膜变化和血栓形成。用转化生长因子β 1（TGF-β 1）和凝血酶刺激原代培养的人脐静脉内皮细胞（HUVEC），通过q-PCR、western blot和ELISA检测HUVEC的表型转化和抗血栓形成功能。最后，通过免疫荧光染色，观察抗凝剂对IVCS模型静脉内皮细胞间质变化的影响。关键发现：我们发现髂静脉压迫诱导EndMT，其抑制可减少血栓形成。进一步的研究表明，接受EndMT的HUVECs失去了抗凝和溶栓功能。有趣的是，凝血酶通过TGF-β/Smad 3信号转导加重EndMT。此外，与野生型（WT）小鼠相比，狭窄的髂静脉EndMT在喂食利伐沙班或因子VII基因敲除小鼠的WT小鼠中减少，这意味着抗凝治疗减轻了IVCS models.Significance的EndMT：我们的研究结果表明，EndMT和血栓形成加强IVCS中的血栓形成，这意味着靶向EndMT可能是预防和治疗IVCS中血栓形成的潜在策略。
Aims: Endothelial-to-mesenchymal transition (EndMT) is a pathophysiological change of vascular endothelium commonly seen in the cardiovascular system. Iliac vein compression syndrome (IVCS) is known to be often associated with intimal hyperplasia and thrombosis. However, whether EndMT exists in IVCS has not yet been reported. The purpose of this study was to investigate the relationship between EndMT and thrombosis in IVCS.Main methods: Using IVCS models in pig and mouse, we detected intimal changes and thrombus in stenotic iliac vein by immunofluorescence staining. Primary human umbilical vein endothelial cells (HUVEC) were stimulated by transforming growth factor beta 1 (TGF-beta 1) and thrombin, and cell phenotypic transition and antithrombotic function of HUVEC were examined through q-PCR, western blot and ELISA. In the end, by immunofluorescence staining, we observed the effect of anticoagulant on interstitial changes of venous endothelial cells in IVCS models.Key findings: We showed that iliac vein compression induced EndMT, of which its inhibition reduced thrombus formation. Further studies showed that HUVECs undergoing EndMT lost their anticoagulation and thrombolytic function. Interestingly, thrombin aggravated EndMT through TGF-beta/Smad3 signaling. Moreover, compared with wild type (WT) mice, EndMT in stenotic iliac vein was reduced in WT mice fed with rivaroxaban or factor VII knockout mice, implying that anticoagulation alleviated EndMT in IVCS models.Significance: Our findings indicate that EndMT and thrombosis reinforce reciprocally in IVCS, implying that targeting EndMT could be a potential strategy in prevention and treatment of thrombosis in IVCS.