on April 17, 2008
Published online before print April 17, 2008, doi: 10.1161/ATVBAHA.108.165753
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Submitted on October 15, 2008
Accepted on April 7, 2008
CD44 Expressed on Both Bone Marrow–Derived and Non–Bone Marrow–Derived Cells Promotes Atherogenesis in ApoE-Deficient Mice
Liang Zhao ;
From the The Wistar Institute (L.Z., E.L., A.M.Z., M.K.M., M.K., P.S.A., J.A.H., E.P.), Philadelphia, Pa; the Department of Medicine (P.S.A., D.J.R., E.P.) and the Immunology Graduate Group (M.K.M., M.K., E.P.), University of Pennsylvania School of Medicine, Philadelphia; and the Ludwig Institute for Cancer Research (E.P.), Philadelphia, Pa.
* To whom correspondence should be addressed. E-mail: pure{at}wistar.org.
Objective—The purpose of this study was to distinguish the contributions of CD44 expressed on bone marrow–derived and non–bone marrow–derived cells to atherosclerosis.
Methods and Results—Using bone marrow chimeras, we compared the contributions of CD44 expressed on bone marrow–derived cells versus non–bone marrow–derived cells to the vascular inflammation underlying atherosclerosis. We show that CD44 in both bone marrow–derived and non–bone marrow–derived compartments promotes atherosclerosis in apoE-/- mice and mediates macrophage and T cell recruitment to lesions in vivo. We also demonstrate that CD44 on endothelial cells (ECs) as well as on macrophages and T cells enhances leukocyte-endothelial cell adhesion and transendothelial migration in vitro. Furthermore, CD44 on vascular smooth muscle cells (VSMCs) regulates their hyaluronan (HA)-dependent migration. Interestingly, in mice lacking CD44 in both compartments, where we observed the least inflammation, we also observed enhanced fibrous cap formation.
Conclusions—CD44 expressed on bone marrow–derived and non–bone marrow–derived cells both promote atherosclerosis in apoE-deficient mice. Furthermore, CD44 plays a pivotal role in determining the balance between inflammation and fibrosis in atherosclerotic lesions which can impact clinical outcome in humans.
Key words: CD44 • atherosclerosis • apoE • bone marrow chimera • fibrous cap