Acute Shear Stress Induces TWIST-Mediated EndMT in Venous Endothelial Cells and Human Long Saphenous Veins.

The use of vein grafts in coronary artery bypass graft surgery is complicated by a high late restenosis rate resulting from the development of intimal hyperplasia. The role of changes in haemodynamics on TGFβ-driven endothelial-to-mesenchymal transition (EndMT) is not fully understood. We identified that arterial shear stress can induce TGFβ/SMAD-dependent EndMT in human umbilical vein endothelial cells (HUVECs), which was regulated by TWIST transcription factors (TWIST1&2), as the selective inhibition of TWIST1 or TWIST2 using siRNA-suppressed EndMT. We noted that brief pretreatment of HUVECs with Dexamethasone can modulate EndMT in response to shear stress. Using spatial cell sequencing in human long saphenous vein segments exposed to acute arterial flow, we identified a cluster of cells with both endothelial and smooth muscle-cell (SMC)-like phenotypes, in which TWIST2 was significantly upregulated. We validated the untargeted spatial findings in segments of veins under acute arterial flow ex vivo. We observed that Dexamethasone can suppress EndMT changes in vein segments by suppressing TGFβ/SMAD/TWIST1&2. This suggests that Dexamethasone brief pretreatment can suppress EndMT changes triggered by acute exposure of long saphenous vein segments to arterial haemodynamics by modulating the TGFβ/SMAD/TWIST1&2 pathway.