The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation

Atherosclerosis causes most acute coronary syndromes and strokes. The patho genesis of atherosclerosis includes recruitment of inflammatory cells to th e vessel wall and activation of vascular cells. CD44 is an adhesion protein expressed on inflammatory and vascular cells. CD44 supports the adhesion o f activated lymphocytes to endothelium and smooth muscle cells. Furthermore , ligation of CD44 induces activation of both inflammatory and vascular cel ls. To assess the potential contribution of CD44 to atherosclerosis, we bre d CD44-null mice to atherosclerosis-prone apoE-deficient mice. We found a 5 0-70% reduction in aortic lesions in CD44-null mice compared with CD44 hete rozygote and wild-type littermates. We demonstrate that CD44 promotes the r ecruitment of macrophages to atherosclerotic lesions. Furthermore, we show that CD44 is required for phenotypic dedifferentiation of medial smooth mus cle cells to the "synthetic" state as measured by expression of VCAM-1. Fin ally, we demonstrate that hyaluronan, the principal ligand for CD44, is upr egulated in atherosclerotic lesions of apoE-deficient mice and that the low -molecular-weight proinflammatory forms of hyaluronan stimulate VCAM-1 expr ession and proliferation of cultured primary aortic smooth muscle cells, wh ereas high-molecular-weight forms of hyaluronan inhibit smooth muscle cell proliferation. We conclude that CD44 plays a critical role in the progressi on of atherosclerosis through multiple mechanisms.