Ryosuke Taniguchi1,2, Yuichi Ohashi1,2, Jung Seok Lee3, Haidi Hu1,4, Luis Gonzalez1, Weichang Zhang1, John Langford1, Yutaka Matsubara1,5, Bogdan Yatsula1, George Tellides1,6,7, Tarek M Fahmy3, Katsuyuki Hoshina2, Alan Dardik1,8,7. 1. Vascular Biology and Therapeutics Program (R.T., Y.O., H.H., L.G., W.Z., J.L., Y.M., B.Y., G.T., A.D.), Yale School of Medicine, New Haven, CT. 2. Division of Vascular Surgery, The University of Tokyo, Japan (R.T., Y.O., K.H.). 3. Department of Biomedical Engineering, Yale University, New Haven, CT (J.S.L., T.M.F.). 4. Department of Vascular and Thyroid Surgery, The First Hospital of China Medical University, Shenyang (H.H.). 5. Department of Surgery and Sciences, Kyushu University, Fukuoka, Japan (Y.M.). 6. Division of Cardiac Surgery, Department of Surgery (G.T.), Yale School of Medicine, New Haven, CT. 7. Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT (G.T., A.D.). 8. Division of Vascular and Endovascular Surgery, Department of Surgery (A.D.), Yale School of Medicine, New Haven, CT.
Abstract
BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-β (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation-critical components of wall thickness-we hypothesized that disruption of TGF-β signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542-an inhibitor of TGF-β receptor I-was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-β receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-β signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-β signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-β signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell-targeted TGF-β inhibition may be a translational strategy to improve AVF patency.
BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-β (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation-critical components of wall thickness-we hypothesized that disruption of TGF-β signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542-an inhibitor of TGF-β receptor I-was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-β receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-β signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-β signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-β signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell-targeted TGF-β inhibition may be a translational strategy to improve AVF patency.
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