Go Kuwahara1, Takuya Hashimoto1, Masayuki Tsuneki1, Kota Yamamoto1, Roland Assi1, Trenton R Foster1, Jesse J Hanisch1, Hualong Bai1, Haidi Hu1, Clinton D Protack1, Michael R Hall1, John S Schardt1, Steven M Jay1, Joseph A Madri1, Shohta Kodama1, Alan Dardik2. 1. From the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT (G.K., T.H., K.Y., R.A., T.R.F., J.J.H., H.B., H.H., C.D.P., M.R.H., J.A.M., A.D.); Department of Cardiovascular Surgery (G.K.) and Department of Regenerative Medicine and Transplantation (G.K., S.K.), Fukuoka University, Japan; Department of Surgery, Veterans Affairs Connecticut Healthcare Systems, West Haven (T.H., K.Y., H.B., H.H., A.D.); Division of Vascular Surgery, Department of Surgery, The University of Tokyo, Japan (T.H., K.Y.); Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan (M.T.); Department of Pathology (M.T., J.A.M.) and Department of Surgery (R.A., T.R.F., J.J.H., C.D.P., M.R.H., A.D.), Yale University School of Medicine, New Haven, CT; and Fischell Department of Bioengineering, University of Maryland, College Park (J.S.S., S.M.J.). 2. From the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT (G.K., T.H., K.Y., R.A., T.R.F., J.J.H., H.B., H.H., C.D.P., M.R.H., J.A.M., A.D.); Department of Cardiovascular Surgery (G.K.) and Department of Regenerative Medicine and Transplantation (G.K., S.K.), Fukuoka University, Japan; Department of Surgery, Veterans Affairs Connecticut Healthcare Systems, West Haven (T.H., K.Y., H.B., H.H., A.D.); Division of Vascular Surgery, Department of Surgery, The University of Tokyo, Japan (T.H., K.Y.); Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan (M.T.); Department of Pathology (M.T., J.A.M.) and Department of Surgery (R.A., T.R.F., J.J.H., C.D.P., M.R.H., A.D.), Yale University School of Medicine, New Haven, CT; and Fischell Department of Bioengineering, University of Maryland, College Park (J.S.S., S.M.J.). alan.dardik@yale.edu.
Abstract
OBJECTIVE: Arteriovenous fistulae (AVF) remain the optimal conduit for hemodialysis access but continue to demonstrate poor patency and poor rates of maturation. We hypothesized that CD44, a widely expressed cellular adhesion molecule that serves as a major receptor for extracellular matrix components, promotes wall thickening and extracellular matrix deposition during AVF maturation. APPROACH AND RESULTS: AVF were created via needle puncture in wild-type C57BL/6J and CD44 knockout mice. CD44 mRNA and protein expression was increased in wild-type AVF. CD44 knockout mice showed no increase in AVF wall thickness (8.9 versus 26.8 μm; P=0.0114), collagen density, and hyaluronic acid density, but similar elastin density when compared with control AVF. CD44 knockout mice also showed no increase in vascular cell adhesion molecule-1 expression, intercellular adhesion molecule-1 expression, and monocyte chemoattractant protein-1 expression in the AVF compared with controls; there were also no increased M2 macrophage markers (transglutaminase-2: 81.5-fold, P=0.0015; interleukin-10: 7.6-fold, P=0.0450) in CD44 knockout mice. Delivery of monocyte chemoattractant protein-1 to CD44 knockout mice rescued the phenotype with thicker AVF walls (27.2 versus 14.7 μm; P=0.0306), increased collagen density (2.4-fold; P=0.0432), and increased number of M2 macrophages (2.1-fold; P=0.0335). CONCLUSIONS: CD44 promotes accumulation of M2 macrophages, extracellular matrix deposition, and wall thickening during AVF maturation. These data show the association of M2 macrophages with wall thickening during AVF maturation and suggest that enhancing CD44 activity may be a strategy to increase AVF maturation.
OBJECTIVE:Arteriovenous fistulae (AVF) remain the optimal conduit for hemodialysis access but continue to demonstrate poor patency and poor rates of maturation. We hypothesized that CD44, a widely expressed cellular adhesion molecule that serves as a major receptor for extracellular matrix components, promotes wall thickening and extracellular matrix deposition during AVF maturation. APPROACH AND RESULTS: AVF were created via needle puncture in wild-type C57BL/6J and CD44 knockout mice. CD44 mRNA and protein expression was increased in wild-type AVF. CD44 knockout mice showed no increase in AVF wall thickness (8.9 versus 26.8 μm; P=0.0114), collagen density, and hyaluronic acid density, but similar elastin density when compared with control AVF. CD44 knockout mice also showed no increase in vascular cell adhesion molecule-1 expression, intercellular adhesion molecule-1 expression, and monocyte chemoattractant protein-1 expression in the AVF compared with controls; there were also no increased M2 macrophage markers (transglutaminase-2: 81.5-fold, P=0.0015; interleukin-10: 7.6-fold, P=0.0450) in CD44 knockout mice. Delivery of monocyte chemoattractant protein-1 to CD44 knockout mice rescued the phenotype with thicker AVF walls (27.2 versus 14.7 μm; P=0.0306), increased collagen density (2.4-fold; P=0.0432), and increased number of M2 macrophages (2.1-fold; P=0.0335). CONCLUSIONS:CD44 promotes accumulation of M2 macrophages, extracellular matrix deposition, and wall thickening during AVF maturation. These data show the association of M2 macrophages with wall thickening during AVF maturation and suggest that enhancing CD44 activity may be a strategy to increase AVF maturation.
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