Reciprocal enhancement of thrombosis by endothelial-to-mesenchymal transition induced by iliac vein compression.

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 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.

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-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.

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.