BACKGROUND: Vein graft stenosis is believed to be the pathophysiologic response of vascular tissue to injury and is the major cause of vein graft failure. Therapeutic interventions might improve with knowledge of the physiologic pathways involved in the hyperplastic response to vascular injury. In this study, our purpose was to identify induced, early pathways that might be important in the human response to vascular injury. STUDY DESIGN: Human saphenous vein from 7 patients was organ cultured or crush injured and cultured for 48 or 72 hours after harvest. Gene expression was determined for syngeneic veins at harvest and at the experimental time points and compared to determine which genes were induced or repressed. Expressed genes (the transcriptional profile) were then assigned to functional physiologic classes. RESULTS: At 72 hours, in both organ-cultured and crush-injured vein, the gene for the Wnt ligand protein (WNT5A) was induced. At 48 hours in the organ-cultured vein only, the gene for the Frizzled protein (FZD2), a subunit of the Wnt receptor complex, was repressed. At 72 hours in injured vein only, the gene for the product of Wnt signaling (WISP1) was induced; the gene for the Wnt-binding, soluble Frizzled-related protein (FRZB) was repressed; and the gene for Dickkopf (DKK1) protein, which binds to the low density lipoprotein receptor-related protein subunit of the Wnt receptor complex, was induced. CONCLUSIONS: Early induction of WNT5A, coupled with the coordinated induction and repression of genes that modulate the Wnt signaling pathway, led to the early, selective induction of WISP1 and no other Wnt-inducible genes. This early, selective expression of a limited gene set might characterize the human vascular response to injury, and could enable development of therapies to treat the clinical sequelae of this response.
BACKGROUND: Vein graft stenosis is believed to be the pathophysiologic response of vascular tissue to injury and is the major cause of vein graft failure. Therapeutic interventions might improve with knowledge of the physiologic pathways involved in the hyperplastic response to vascular injury. In this study, our purpose was to identify induced, early pathways that might be important in the human response to vascular injury. STUDY DESIGN:Human saphenous vein from 7 patients was organ cultured or crush injured and cultured for 48 or 72 hours after harvest. Gene expression was determined for syngeneic veins at harvest and at the experimental time points and compared to determine which genes were induced or repressed. Expressed genes (the transcriptional profile) were then assigned to functional physiologic classes. RESULTS: At 72 hours, in both organ-cultured and crush-injured vein, the gene for the Wnt ligand protein (WNT5A) was induced. At 48 hours in the organ-cultured vein only, the gene for the Frizzled protein (FZD2), a subunit of the Wnt receptor complex, was repressed. At 72 hours in injured vein only, the gene for the product of Wnt signaling (WISP1) was induced; the gene for the Wnt-binding, soluble Frizzled-related protein (FRZB) was repressed; and the gene for Dickkopf (DKK1) protein, which binds to the low density lipoprotein receptor-related protein subunit of the Wnt receptor complex, was induced. CONCLUSIONS: Early induction of WNT5A, coupled with the coordinated induction and repression of genes that modulate the Wnt signaling pathway, led to the early, selective induction of WISP1 and no other Wnt-inducible genes. This early, selective expression of a limited gene set might characterize the human vascular response to injury, and could enable development of therapies to treat the clinical sequelae of this response.