Anti-proliferative and anti-inflammatory effects of topical MAPK inhibition in arterialized vein grafts

ABSTRACT Vein graft failure following bypass surgery is a frequent and important clinical problem. The vascular injury caused by arterialization is responsible for vein graft intimal hyperplasia, a lesion generated by medial smooth muscle cell proliferation and migration into the intima, increased extracellular matrix deposition, and formation of a thick neointima. Development of the neointima into a typical atherosclerotic lesion and consequent stenosis ultimately result in vein graft failure. Endothelial damage, inflammation, and intracellular signaling through mitogenactivated protein kinases (MAPKs) have been implicated in the early stages of this process. We therefore investigated the effects of topical inhibition of ERK‐1/2 MAPK activation on vascular cell proliferation and apoptosis, and on the inflammatory response in a canine model of vein graft arterialization. For this purpose, vein grafts were incubated with the MEK‐1/2 inhibitor, UO126, ex vivo for 30 min before grafting. This treatment effectively abolished arterializationinduced ERK‐1/2 activation, decreased medial cell proliferation, and increased apoptosis. UO126 treatment also inhibited the vein graft infiltration by myeloperoxidase‐positive inflammatory cells that follows vein graft arterialization. Thus, topical ex vivo administration of MAPK inhibitors can provide a pharmacological tool to prevent or reduce the vascular cell responses that lead to vein graft intimal hyperplasia and graft failure.