Silencing of FSP-1 in Bone Marrow Cells Suppresses Neointima Formation in Vein Graft

【摘要】：正Arteriovenous(AV) grafts are commonly created to relieve angina or function as an access for hemodialysis.Failure of these grafts is characterized by hyperplasia of venous smooth muscle cells(SMCs),neointima formation and atherosclerosis.Several processes including endothelial dysfunction and neointima cell hyperplasia are present in failed vein grafts.The pathogenesis of this lesion is incompletely understood.In this study we sought to identify the molecular and cellular signalings causing neointimal formation in AV grafts.We have identified that bone marrow(BM)-derived fibroblast specific protein -1(FSP-1)~+ cells are major components of remodeled AV grafts.BM-derived,FSP-1~+ cells are attracted to the graft via a SDF-lα-dependent mechanism and induce transendothelial invasion of inflammatory cells into the neointima.There are several novel discoveries in this study:1) we found that after creation of a vein graft,there is rapid loss of endothelial cells followed by deposition of platelets on the denuded surface.These platelets secrete the chemokine stromal cell-derived factor-la(SDF-lα). It recruits bone marrow(BM)-derived cells that express the SDF-lαreceptor CXCR4;2) we found that homing of FSP-1~+cells was dependent on platelete-derived SDF-lα.We also found that the FSP-1~+cells migrated into the vein graft media and secreted FSP-1;3)co-culture and manipulation of FSP-1 expression in vivo were found to stimulate proliferation of SMC and SMC hyperplasia leads to vein graft failure.