Abstract 16205: The Role of Stem Cell Factor (SCF)/c-Kit Signaling in Vein Stenosis
Background: Neointimal hyperplasia is the fundamental lesion contributing to the failure of coronary bypass grafts and arteriovenous (AV) fistulas in hemodialysis patients. This study aims to demonstrate the role of the Stem Cell Factor (SCF) and its receptor c-kit in the mobilization of pathogenic progenitor cells towards the neointima in an experimental model of AV fistula failure.
Methods and Results: AV fistulas were created in Lewis rats by anastomosing the left renal vein to the abdominal aorta after unilateral nephrectomy. This model recapitulates the salient features of AV fistulas in humans including aggressive neointima formation and vascular stenosis. The expression of SCF and its receptor c-kit in the fistula wall was initially measured by TaqMan RT-qPCR. The expression of c-kit and SCF genes was increased 4.6 ±0.31 and 3.4 ± 0.23 folds in AV fistulas (n=4) with respect to the renal vein of sham operated animals. Then, cells expressing c-Kit were located within the fistula wall using immunofluorescence confocal microscopy. c-kit+ cells were found within the neointima and adventitia of the venous limb of the fistula. c-kit+ cells were detectable at day 3 (125 ± 23 cells/mm2) reaching its maximum at day 14 (435± 72 cells/mm2) and then decreased to non-significant levels at day 30 (35±15 cells/mm2). These cells only turned positive for SMA in the neointima. We also sought for the SCF in the fistula wall. Interestingly, SCF was only and largely expressed in the neointima of the fistula wall. Finally to demonstrate the essential role SCF/c-kit signaling on vein stenosis, rats carrying AV fistulas where treated with Imatinib mesylate (Gleevec) (5mg/Kg/d) for seven days. Gleevec a tyrosine kinase inhibitor that selectively blocks c-kit produced a 3-folds reduction in neointimal thickness in treated versus control groups (0.093±0.006 vs. 0.030±0.0008, p=0.0026).
Conclusion: Our results demonstrate that the interaction between SCF and the c-kit progenitor cells in the fistula wall pay an important role during neointimal formation in AV fistulas.
- © 2010 by American Heart Association, Inc.