Abstract 12501: Critical Role of Hyaluronan Derived From Vascular Smooth Muscle Cells in Neointimal Formation After Vascular Injury
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. Here, we investigated the its role in neointimal formation after vascular injury using conditional transgenic mice specifically overexpressing murine HA synthase 2 (HAS2) gene in vascular smooth muscle cells (VSMCs) by Cre-mediated transgene activation (HAS-CreSM22alpha mice).
Methods and Results: 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. Cuff-induced neointimal formation was dramatically enhanced in HAS-CreSM22alpha mice, compared with that in wild-type and CreSM22alpha (control) mice (I/M ratio: 1.45±0.03 vs. 0.54±0.07 (control) and 0.50±0.04 (CreSM22alpha), p<0.0001). We further examined the effect of 4-methylumbelliferone (4-MU), a specific inhibitor of HA, 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 demonstrated that HA production and migration, but not proliferation, were significantly decreased by 4-MU treatment in cultured rat aortic VSMCs.
Conclusions: These findings suggest that HA derived from VSMCs is critical for neointimal formation after vascular injury and identify HA as a novel therapeutic target for atherosclerosis and restenosis after percutaneous coronary intervention.
- © 2010 by American Heart Association, Inc.