CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation

• DOI: 10.1161/atvbaha.117.309385
• Publication Date: 2017-04-28T01:00:20Z
• Authors: Go Kuwahara; Takuya Hashimoto; Masayuki Tsuneki; Kota Yamamoto; Roland Assi; Trenton R. Foster; Jesse J. Hanisch; Hualong Bai; Haidi Hu; Clinton D. Protack; Michael R. Hall; John S. Schardt; Steven M. Jay; Joseph A. Madri; Shohta Kodama; Alan Dardik
• Keywords: Inflammation; Male; Mice, Knockout; 0301 basic medicine; Time Factors; Genotype; Macrophages; Vena Cava, Inferior; Elastin; Extracellular Matrix; Mice, Inbred C57BL; 03 medical and health sciences; Arteriovenous Shunt, Surgical; Hyaluronan Receptors; Phenotype; Animals; Aorta, Abdominal; Collagen; Hyaluronic Acid; Chemokine CCL2; Signal Transduction

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.