Abstract
Autogenous vein grafts remain the gold standard conduit for arterial bypass, particularly for the treatment of critical limb ischemia. Vein graft adaptation to the arterial environment, i.e., adequate dilation and wall thickening, contributes to the superior performance of vein grafts. However, abnormal venous wall remodeling with excessive neointimal hyperplasia commonly causes vein graft failure. Since the PREVENT trials failed to improve vein graft outcomes, new strategies focus on the adaptive response of the venous endothelial cells to the post-surgical arterial environment. Eph-B4, the determinant of venous endothelium during embryonic development, remains expressed and functional in adult venous tissue. After surgery, vein grafts lose their venous identity, with loss of Eph-B4 expression; however, arterial identity is not gained, consistent with loss of all vessel identity. In mouse vein grafts, stimulation of venous Eph-B4 signaling promotes retention of venous identity in endothelial cells and is associated with vein graft walls that are not thickened. Eph-B4 regulates downstream signaling pathways of relevance to vascular biology, including caveolin-1, Akt, and endothelial nitric oxide synthase (eNOS). Regulation of the Eph-B4 signaling pathway may be a novel therapeutic target to prevent vein graft failure.