OBJECTIVE: Intimal hyperplasia and surface thrombogenicity are major factors in the high failure rate of synthetic small-diameter bypass grafts. Vascular endothelial growth factor is a potent stimulus for endothelial growth, and its provision in a fibrin matrix coating at the luminal graft surface may hold a key to spontaneous graft endothelialization and improved graft patency. METHODS: Pigs underwent bilateral carotid artery interposition of expanded polytetrafluoroethylene grafts either impregnated with fibrin (n = 11)--engineered to locally release vascular endothelial growth factor121 (vascular endothelial growth factor-fibrin; n = 11)--or left uncoated (n = 12). Graft patency was assessed by quantitative carotid angiography followed by graft histomorphometry at the 1-month experimental end point. RESULTS: Patency rates were not significantly different between study groups. Grafts coated with fibrin or vascular endothelial growth factor-fibrin exhibited significantly increased angiographic narrowing at the proximal anastomosis (for both P < .05 vs uncoated) and no difference at the distal anastomosis and the grafts' middle. Histological analysis showed 80% to 90% endothelial coverage and buildup of intima throughout the lengths of all grafts. Examination of the grafts' midportion revealed significantly enlarged neointimal layers of smooth muscle actin-positive cells in grafts coated with vascular endothelial growth factor-fibrin (242 +/- 47 microm2/micron) and fibrin (177 +/- 41 microm2/micron), compared with uncoated grafts (131 +/- 39 microm2/micron) (for both P < .05 vs uncoated). This thickening could not be explained by enhanced inflammation or vessel wall angiogenesis, which were minimal at the experimental end point. CONCLUSIONS: Fibrin and vascular endothelial growth factor produced effects deleterious to graft healing, by increasing the narrowing at proximal anastomosis and neointimal growth beyond that seen in uncoated grafts. It may reflect direct activation by exogenous vascular endothelial growth factor of vascular smooth muscle cells.