Abstract 17707: The Degree of Inflammation Dictates the Role of Smooth Muscle Cell-Specific CD44 and its Effect on Neointimal Formation in Atherosclerosis versus Vascular Injury
Proliferation of vascular smooth muscle cells (VSMCs) and their accompanying matrix production is fundamental to neointima formation, a hallmark of cardiovascular disease (CVD). We previously showed that the HA-receptor CD44 has bi-functional effects on VSMC proliferation and activation. Global deletion of CD44 in atherosclerosis (apoE-/- mice) suppresses lesion burden. Conversely, in a model of vascular injury (wildtype mice), global deletion of CD44 exacerbates the injury response. As atherosclerotic lesions are highly inflammatory, the aim of this study was to determine if the biological response to CD44 was directed, in part by, the degree of local inflammation, and thus account for the contradictory effects of CD44 on neointima formation in atherosclerosis versus after vascular injury. Under high inflammatory conditions (in apoE-/- mice), vascular injury was more severe compared to the low inflammatory control (wildtype mice). However, whereas CD44-deletion enhanced the injury response in wildtype mice, it did not further exacerbate the injury response in apoE-/- mice (apoE-/-.CD44-/-), compared to apoE-/-. These data suggest that the protective effect of CD44 seen in wildtype mice was overcome in the face of a more inflammatory milieu presented in apoE-/- mice. Neointimal architecture following vascular injury in apoE-/-.CD44-/- mice favored a more fibrotic phenotype, associated with increased matrix content, cell proliferation and reduced inflammation, suggesting an important role for VSMC-specific CD44 in neointimal formation. This was further supported upon VSMC-specific deletion of CD44 in apoE-/- mice, where atherosclerotic lesion burden was attenuated compared to apoE-/- mice. Taken together, this suggests that CD44 may be targeted in the development of therapeutic regimens for atherosclerosis without increasing the risk of restenosis in the context of percutaneous interventions for the treatment of CVD.
- © 2013 by American Heart Association, Inc.