Abstract 16874: Critical Role of Hyaluronan Derived From Macrophages in Neointimal Formation After Vascular Injury in Mice
Background: Hyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its cell-specific role in macrophages by using a cre-lox conditional transgenic (cTg) strategy.
Methods and Results: HA was found to be expressed in neointimal lesions in humans with atherosclerosis and after wire-mediated vascular injury in wild-type (C57BL/6) mice. Oral treatment with 4-methylumbelliferone, a specific inhibitor of HA production, significantly attenuated neointimal formation after vascular injury (I/M ratio: 1.84 ± 0.07 vs. 0.63 ± 0.03, p<0.0001). In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced murine macrophages activation, including migration, and production of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1. Because HAS2 is thought to be a key enzyme responsible for HA production in macrophages, we generated cTg mice that overexpress the murine HAS2 gene specifically in macrophages (cHAS2/CreLys mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury (I/M ratio: 1.42 ± 0.03 (cHAS2/CreLys ) vs. 0.54 ± 0.07 (cHAS2) and 0.50 ± 0.04 (CreLys), p<0.0001). Further, HA-overexpressing macrophages isolated from cHAS2/CreLys mice showed augmented migration, and production of inflammatory cytokines.
Conclusion: Macrophages-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease.
- © 2013 by American Heart Association, Inc.