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1 Radiology, Mayo Clinic, Rochester, Minnesota, United States
2 Radiology, Mayo Clinic, Rc, Minnesota, United States
3 Surgery, Mayo Clinic, United States
4 Vascular Surgery, Mayo Clinic, Rochester, Minnesota, United States
5 Internal Medicine, Mayo, Rochester, Minnesota, United States
6 Univeristy of Minnesota, United States
7 Mayo Clinic College of Medicine, United States
8 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
* To whom correspondence should be addressed. E-mail: misra.sanjay{at}mayo.edu.
Venous injury and subsequent venous stenosis formation are responsible for hemodialysis graft failure. Our hypothesis is that these pathologic changes are in part related to changes in wall shear stress that results in activation of matrix regulatory proteins causing subsequent venous stenosis formation. We examined the serial changes in wall shear stress (WSS), blood flow, luminal vessel area, and the corresponding histologic, morphometric, and kinetic changes of several matrix regulatory proteins including VEGF-A, its receptors, MMP-2, MMP-9, TIMP-1, and TIMP-2. Wall shear stress was estimated by obtaining blood flow and luminal vessel area by performing phase contrast magnetic resonance imaging with magnetic resonance angiography in 21 animals at 1 day after graft placement and prior to sacrifice at day 3 (N=7), day 7 (N=7), and day 14 (N=7). At all time points, the mean wall shear stress at the vein-to-graft anastomosis was significantly higher than the control vein (P<0.05). The wall shear stress had a bimodal distribution with peaks at day 1 and day 7 followed by a significant reduction in WSS by day 14 (P<0.05, when compared to day 7) and a decrease in luminal vessel area when compared to control vessels. By day 3, there was a significant increase in VEGF-A and pro MMP-9 followed by at day 7 increased pro MMP-2, active MMP-2, and VEGFR-2 (P<0.05), and by day 14, increased VEGFR-1 and TIMP-1 (P<0.05) at the vein-to-graft anastomosis when compared to control vessels. Over time, the neointima thickened and was composed primarily of 
-smooth muscle actin positive cells with increased cellular proliferation. Our data suggest that hemodialysis graft placement leads to early increases in wall shear stress, VEGF-A and pro MMP-9, followed by subsequent increases in pro MMP-2, active MMP-2, VEGFR-2 and VEGFR-1 and TIMP-1, which may contribute to the development of venous stenosis.
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