Saphenous vein graft (SV.G) neointimal thickening post coronary artery bypass grafting (CABG) is an adaptive mechanism by the SVG to withstand the hemodynamic stress that results from the change in environment from the venous to the arterial circulation. However, this adaptive response often becomes pathologic resulting in focal narrowings or graft closure. In favorable outcomes, the intimal growth reaches a steady state where luminal area and functional integrity of the vein graft is maintained. In this setting, vessel wall homeostatsis may be maintained by the intact endothelium which exerts its regulatory influence on the process of neointimal thickening by production of soluble factors. Preliminary evidence suggests that one of the soluble factors may be plasminogen activator inhibitory (PAI-1) and its increase in expression appears to be flowmediated. PAI-1 has been shown to play a role in smooth muscle cell (SMC) migration and neointimal thickening. Specific hypothesis to be tested in this proposal is that enclothelial (EC) PAI-1 expression is one of the predominant mechanisms responsible for flow-mediated endothelial control of intimal changes in arterial conduits.
In specific aim 1, using a perfused transcapillary co-culture in vitro system, we will determine if there is an EC influence on SIVIC migration in response to pulsatile flow.
In specific aim 2, we will determine if pulsatile flow alters EC PAI-1 expression in the presence of SMC.
In specific aim 3, to determine if flow-induced EC PAI-1 -expression is one of the predominant mechanisms behind endothelial influence on SMC migration, we will study the following combinations using mutant null mice technology: (i) the migratory behavior of murine wildtype SMC co-cultured with PAI-1 null EC and (ii) the effect of active PAI-1 repletion on the migratory behavior of wildtype SMC co-cultured with PAI-1 null EC. In specific Im 4, to determine if SMC PAI-1 is a co-participant in regulating the process of SMC migration, we will tudy the migratory behavior of PAI-1 null SIVIC co-cultured with wildtype EC.
In specific aim 5, to etermine if SVG patency is associated with an altered expression of PAI-1 mRNA in vein graft luminal ndothelial cells, we will perform comparative analysis of PAI-1 expression in EC from patent SVG vs. occluded SVG using in situ hybridization. Identifying the factors that inhibit vein graft neointimal thickening will allow the development of target-directed pharmacological interventions to control this process.
| Cullen, John P; Nicholl, Suzanne M; Sayeed, Shariq et al. (2004) Plasminogen activator inhibitor-1 deficiency enhances flow-induced smooth muscle cell migration. Thromb Res 114:57-65 |
| Redmond, E M; Cullen, J P; Cahill, P A et al. (2001) Endothelial cells inhibit flow-induced smooth muscle cell migration: role of plasminogen activator inhibitor-1. Circulation 103:597-603 |
