Identification of early pathophysiological events underlying venous coronary bypass stenosis by a mechano-biology approach

Saphenous vein graft disease represents an unresolved problem in coronary artery bypass grafting. After surgery, progressive modification in the vein wall occurs, leading to occlusion of the graft lumen. This process, called intima hyperplasia, involves the participation of vein-resident cells as well as the recruitment of vein-extrinsic cells. Arterial wall strain has recently emerged as one of the factor that can contribute to the pathogenesis of the vein graft disease. Therefore, in collaboration with Department of Bioengineering, Politecnico di Milano we developed a culture system for the ex vivo pressure stimulation of vein segments. This new ex vivo vein culture system is able to reproduce the wall strain typical of the arterial circulation. The ex vivo vein culture system (ECVS) adopted in this project has been validated and proved as a valuable, reliable, easy handling and versatile tool for studying arterial pressure events triggered in VGD. The biological data achieved confirm an important contribution of the arterial-like wall strain in SV structural and biochemical changes, activation of vessel resident cells and in the expression of molecular signals involved in the pathogenesis of IH. Using this system, we found that either venous- or arterial-specific pressure regimens induced vein pro-pathologic commitment involving upregulation of Matrix Metallo-Proteases 2/9, and induction of microRNAs-21/146a/221. By contrast, arterial-like pressure caused a significant morphological rearrangement of the vein, a suppression of Tissue Inhibitor of Metallo Protease-1, an enhanced expression of TGF-β1 and BMP-2 mRNAs and, finally, the upregulation of microRNAs-138/200b/200c. In coronary-pressure stimulated vessels, the density of the adventitial vasa vasorum was significantly increased. This was accompanied by an increased presence of cells co-expressing NG2, CD44 and SM22α markers in the adventitia, identifying them as multipotent mesenchymal cells/smooth muscle cells progenitors with a pericyte origin. An increase in Histone H3 Lysine 4 methylation and histone H4 Lysines 9/16 acetylation levels was finally found in adventitial cells and vasa vasorum. The present findings suggest a mechanistic role of the arterial-like pulsatile pressure in reinforcement of SV-resident cells pro-pathologic commitment in vein bypass failure, by activation of mechanical-dependent transcriptional circuitries and of pericyte-derived cells located in the vessel adventitia. The ultimate goal of this project is to find a treatment that can prevent, avoid or reduce the incidence of the vein graft disease in patients subjected to bypass surgery with saphenous vein. This treatment could include one or more targets identified in this work focusing on the early stage of the pathological adaptation of the SV to the new hemodynamic environment.