Vein graft neointimal
hyperplasia involves proliferation and migration of vascular smooth muscle cells into the vessel intima, and ultimately engenders accelerated
atherosclerosis and vein graft failure. Since a myriad of stimuli provoke smooth muscle cell proliferation, molecular
therapies for vein graft disease have targeted mechanisms fundamental to all cell proliferation - the 'cell-cycle' machinery. Preclinically, the most successful of these
therapies has been
edifoligide (E2F decoy), a double-stranded
oligodeoxynucleotide that binds to the
transcription factor known as E2F. Recently, PRoject of Ex vivo vein GRaft Engineering via Transfection (PREVENT) III and IV demonstrated that
edifoligide failed to benefit human vein grafts employed to treat lower-extremity
ischemia and
coronary heart disease, respectively. The clinical failure of
edifoligide calls into question previous models of vein graft disease and lends credence to recent animal studies demonstrating that vein graft arterialization substantially involves the immigration into the vein graft of a variety of vascular progenitor cells. Future vein graft disease
therapies will likely target not only proliferation of graft-intrinsic cells, but also immigration of graft-extrinsic cells.