Veterans are disproportionately affected by peripheral artery disease (PAD) and coronary artery disease (CAD) because of high rates of tobacco use in the veteran population. Up to one-third of the saphenous vein bypass grafts performed for either PAD or CAD fail secondary to a process called neointimal hyperplasia. We have established a new model to study saphenous vein grafts by implanting human saphenous veins into immunodeficient nude rats. This model develops significant neointimal hyperplasia, unlike prior animal models using animal vein grafts. Our previous work on human saphenous vein grafts suggest that adventitial cells may prevent neointimal hyperplasia and graft failure. We have also been testing a novel therapeutic agent SB-030, which when administered luminally, decreases the neointimal hyperplasia reaction to angioplasty-induced arterial injury in humans presumably by inhibiting smooth muscle cell proliferation. This proposal will test whether adventitial cells can be used therapeutically to decrease neointimal hyperplasia. In addition, we will test whether inhibiting adventitial cell proliferation by applying SB-030 to the adventitia causes increased neointimal hyperplasia. In contrast, we expect luminal application of SB-030 will decrease neointimal hyperplasia by inhibiting smooth muscle cells. These results will be relevant for future treatment of vein grafts with SB- 030 or other therapeutics that target both adventitial cells and medial smooth muscle cells. Successful completion of this proposal will better establish the new model, demonstrate whether adventitial cells reduce neointimal hyperplasia, and determine whether adventitial or luminal application of a novel therapeutic will best inhibit neointimal hyperplasia. This will lead to new therapies to improve the success of vein bypass grafts for patients.