Abstract 11456: Pressure-Driven Remodeling in Human Saphenous Veins: Evidences of Mechano-Epigenetic Effects in Intima Hyperplasia Associated to Coronary Artery By-Pass Grafting
Background: Saphenous vein (SV) graft disease represents an unresolved problem in coronary artery bypass grafting (CABG). After surgery, progressive structural modifications in the vein wall occur with gradual occlusion of graft lumen. This is due to a complex process, called intima hyperplasia, involving activation of vein-resident smooth muscle cells (SMCs).
Methods and Results: We have recently devised a novel ex vivo vein culture system, able to reproduce the wall strain associated to coronary-like pressure. This system was used to expose human SV segments (5 cm length) to CABG-like (pulsatile pressure: 80-120mmHg for 10 min alternated with medium recirculation at 1 ml/min for 2min) or venous perfusion (VP, steady flow: 3 ml/min at 5 mmHg luminal pressure) conditions, for 7 days period. At the end of the experiment, SV segments were examined by histology/immunofluorescence and proteomic techniques. Computer-assisted morphometry indicated a significant reduction of the vessel thickness (327.3±40.5μm vs. 575.5±60.8μm; P<0.05; n=6; t-test) and an increase in the lumen perimeter (12.10±1.14mm vs. 8.77±0.49mm; P<0.05; n=6; t-test) in CABG vs. non-stimulated SV segments; these changes were not observed in VP-exposed SVs. In CABG-like, but not VP-stimulated SVs, remodeling of the smooth muscle cells layers in the media, evident ruptures of the endothelial cells layer and significant increase in cellular proliferation (%Ki-67+ cells, CABG vs. VP SVs: 46.33±2.9 vs. 29.29±2.14; P<0.001; n=3; t-test) were also observed. These changes were accompanied by upregulation of matrix remodeling enzymes MMP2/9 and differential activation of TIMP-1. Exposure of SV segments to arterial-like pressure induced changes in the Histone H3 lysine 4 methylation and histone H4 lysine 9 and 16 acetylation levels, especially in adventitial cells and cells of the vasa vasorum. This correlated with an increase in vasa vasorum thickness, their structural disarrangement and downregulation of typical endothelial markers CD31 and vWF.
Conclusions: The present findings suggest an unexpected ‘mechano-epigenetic’ mechanism involved in pro-pathologic commitment of SV-resident cells, particularly in adventitial cells with SMC progenitor characteristics.
- © 2013 by American Heart Association, Inc.