CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation

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 (ECM) components, promotes wall thickening and ECM deposition during AVF maturation. Approach and Results AVF were created via needle puncture in wild-type (WT) C57BL/6J and CD44 knockout (KO) mice. CD44 mRNA and protein expression was increased in WT AVF. CD44 KO mice showed no increase in AVF wall thickness (8.9 μm vs. 26.8 μm; P = 0.0114), collagen density, and hyaluronic acid density, but similar elastin density when compared to control AVF. CD44 KO mice also showed no increase in VCAM-1 expression, ICAM-1 expression and MCP-1 expression in the AVF compared to controls; there were also no increased M2 macrophage markers (TGM2: 81.5 fold, P = 0.0015; IL-10: 7.6 fold, P = 0.0450) in CD44 KO mice. Delivery of MCP-1 to CD44 KO mice rescued the phenotype with thicker AVF walls (27.2 μm vs. 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, ECM 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.

An Implanted Blood Vessel Support Device for Arteriovenous Fistulas: A Randomized Controlled Trial

“…11 The complex hemodynamic profile is believed to stimulate remodeling and intimal hyperplasia-related failure through a pathway that involves endothelial cell (EC) activation and the secretion of prothrombotic and vasoconstrictive factors, known to promote intimal growth through proliferation and migration of vascular smooth muscle cells and extracellular matrix deposition. 12 In vitro studies have evaluated EC responses to different flow rates and related shear stress patterns, 13 linking unidirectional WSS and reduced circumferential strain with EC quiescence and outward vein remodeling.…”

Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency

“…Acquisition of dual arterial-venous identity during AVF maturation, e.g. colocalization of cells expressing EphrinB ligands with cells expressing EphB receptors, may be an important mechanism of venous remodeling; however, the relative contributions of EphrinB- and EphB- expressing cells that are native cell components of the vessel wall, or infiltrating cells such as inflammatory cells or M2 macrophages 37 , is not clear.…”

Analysis of differential gene expression of heart failure based on Gene Expression Omnibus database

“…CD44 is a multifunctional transmembrane glycoprotein, which interacts with hyaluronic acid to mediate the migration and proliferation of endothelial cells, macrophages, broblasts and other cell types. Meanwhile, it was involved in the stimulation of Tumor necrosis factorα/Nuclear-factor-kappa-B (TNFα/NFkB) signaling pathway to promote the production of in ammation and development of cardiac brosis [36][37][38], causing the remodeling of extracellular matrix. Excessive remodeling of the extracellular matrix was likely to result in heart failure.…”