Molecular biology of graft occlusion

Whatever the method, the biologic price of restitution of arterial flow through or around an obstructed artery is injury to the arterial wall. The artery mounts a healing response that in 30% to 60% of procedures exceeds the need. The result is formation of a lumen-narrowing lesion composed of smooth muscle cells and extracellular matrix with varying amounts of atherosclerotic components. The primary player appears to be the smooth muscle cell. For four decades the standard model for studying these events has been catheter denudation of arterial endothelium in small animals. Molecular biology has provided an enormous amount of new information including growth factors, adhesion molecules, receptor binding sites, and molecules that up- or down-regulate or maintain a steady state of expression of numberless genes in the arterial wall. Predictably, means of inhibiting these molecular events have been found. That their clinical trials have been universally disappointing should not be surprising given that the animal in which the discoveries were made--the rat--is not normally susceptible to atherosclerosis and the histology of the rat artery only approximates that of the human. Nevertheless, reason for optimism exists because of our increasing understanding of the injury response. Recent developments include the use of blocking antisense oligonucleotides, blocking antibodies, gene transfer trials, and early investigations into the role of the immune system.