The Second Affiliated Hospital of Soochow University, Suzhou, China; Department of Vascular Surgery, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
The Second Affiliated Hospital of Soochow University, Suzhou, China; Department of Vascular Surgery, The First People's Hospital of Wuxi, Wuxi, China.
Life Sci. 2019 Sep 15;233:116659. doi: 10.1016/j.lfs.2019.116659. Epub 2019 Jul 16.
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.
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 β1 (TGF-β1) 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.
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-β/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.
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.
内皮细胞向间充质细胞转化（EndMT）是心血管系统中常见的血管内皮病理生理改变。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，IVCS 中是否存在 EndMT 尚未有报道。本研究旨在探讨 IVCS 中 EndMT 与血栓形成的关系。
利用猪和小鼠的 IVCS 模型，通过免疫荧光染色检测狭窄髂静脉的内膜变化和血栓。用转化生长因子β1（TGF-β1）和凝血酶刺激原代人脐静脉内皮细胞（HUVEC），通过 q-PCR、western blot 和 ELISA 检测 HUVEC 细胞表型转化和抗血栓功能。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。
我们表明，髂静脉压迫诱导了 EndMT，其抑制减少了血栓形成。进一步的研究表明，发生 EndMT 的 HUVEC 失去了抗凝和溶栓功能。有趣的是，凝血酶通过 TGF-β/Smad3 信号加重了 EndMT。此外，与野生型（WT）小鼠相比，在给予利伐沙班或因子 VII 敲除小鼠的 WT 小鼠中，狭窄髂静脉中的 EndMT 减少，这表明抗凝在 IVCS 模型中减轻了 EndMT。
我们的研究结果表明，IVCS 中的 EndMT 和血栓形成相互促进，提示靶向 EndMT 可能是预防和治疗 IVCS 中血栓形成的一种潜在策略。
