Investigating shear-dependent modulation of endothelial-vascular smooth muscle cell communication

Abstract

The long saphenous vein (LSV) is a commonly used conduit in coronary artery bypass graft surgery, however it is susceptible to vein graft failure (VGF). Venous endothelial cells (vECs) within the LSV are adapted to low-magnitude fluid shear stress (FSS), however they are exposed to significantly increased FSS upon grafting into the arterial circulation. EC-to-vascular smooth muscle cell (VSMC) communication is essential for maintaining vascular homeostasis and therefore increased FSS may alter the communication and be a key modulator of VGF.

It was hypothesised that acute exposure of vECs to arterial FSS results in pathological changes to the vEC secretome which contribute to VGF. The acute response of vECs to arterial FSS was characterised by the increase in inflammatory adhesion molecules and NFκB activity, altered cell and nuclear morphology, reduced cell-cell contact and increased apoptosis and modified composition of the secretome. The modified composition of the vEC secretome caused reduced expression of contractile proteins, decreased contractility and increased apoptosis in VSMCs. Proteomic analysis identified four proteins of interest (thrombospondin-1,fibroleukin, a disintegrin and metalloproteinase with thrombospondin motifs 4, and plateletderived growth factor A) which were investigated for their contribution to the pathologicalchanges observed in vECs exposed to arterial FSS and in VSMCs treated with vEC secretome. Subsequently, anti-inflammatory interventions were investigated to determine their potential to reduce the effects of arterial FSS and improve vein graft patency. Dual treatment with atorvastatin/dexamethasone reduced inflammatory adhesion molecule expression and EC and VSMC apoptosis which may improve vein graft patency.

In summary the findings demonstrate that acute exposure of vECs to arterial FSS causes changes in the composition of the secretome which modulates vEC and VSMC behaviour and may contribute to VGF. Additionally treatment with anti-inflammatory agents may reduce the impact of arterial FSS and therefore improve vein graft patency.

Date of Award	10 Dec 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Sarah J George (Supervisor), Jason L Johnson (Supervisor) & Raimondo Ascione (Supervisor)