Abstract 13888: Critical Role of Hyaluronan in Neointimal Formation after Vascular Injury in Mice
Background: Hyaluronan (HA), a non-sulfated glycosaminoglycan, is a primary component of extracellular matrix that accumulates in the lesions of atherosclerosis and restenosis after percutaneous coronary intervention. However, the role of HA in these lesions remains unclear. The purpose of this study is to investigate the role of HA in neointimal formation after vascular injury and its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy.
Methods and Results: HA was expressed in neointimal lesion in human atherosclerosis. We produced 2 types of vascular injury, cuff-mediated and wire-mediated injury, in femoral artery and found that marked HA expression in the injury-induced neointimal lesion of wild-type (C57BL/6) mice. We further examined the effect of 4-methylumbelliferone (4-MU), a specific inhibitor of HA production, on neointimal formation after wire-mediated injury. Neointimal formation was significantly attenuated by the oral treatment with 4-MU (I/M ratio: 2.10±0.08 vs. 0.63±0.03, p<0.0001). Moreover, In vitro experiments revealed that low molecular weight HA (LMW-HA) stimulated VSMC behavior, such as migration, proliferation, and production of inflammatory cytokines and reactive oxygen species in cultured mouse aortic VSMCs. The migration and proliferation was mediated through CD44/RhoA and CD44/ERK1/2 pathways, respectively. Since HA synthase 2 (HAS2) was predominantly expressed in the injured arteries, we generated cTg mice overexpressing murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22alpha mice) and demonstrated that HA overexpression in the media markedly enhanced neointimal formation after a cuff-mediated vascular injury (I/M ratio: 1.45±0.03 vs. 0.54±0.07 (cHAS2) and 0.50±0.04 (CreSM22alpha), p<0.0001). Furthermore, HA-overexpressed VSMCs isolated from cHAS2/CreSM22alpha mice augmented the VSMC behavior.
Conclusions: These findings suggest that VSMC-derived HA promoted neointimal formation after vascular injury and identify HA as a novel therapeutic target for atherosclerosis and restenosis after percutaneous coronary intervention.
- © 2012 by American Heart Association, Inc.