['To identify early changes in vascular gene expression mediated by CD44 that promote atherosclerotic disease in apolipoprotein E (apoE)-deficient (apoE-/-) mice.', 'We demonstrate that CD44 is upregulated and functionally activated in aortic arch in the atherogenic environment of apoE-/- mice relative to wild-type (C57BL/6) controls. Moreover, CD44 activation even in apoE-/- mice is selective to lesion-prone regions because neither the thoracic aorta from apoE-/- mice nor the aortic arch of C57BL/6 mice exhibited upregulation of CD44 compared with thoracic aorta of CD57BL/6 mice. Consistent with these observations, gene expression profiling using cDNA microarrays and quantitative polymerase chain reaction revealed that approximately 155 of 19,200 genes analyzed were differentially regulated in the aortic arch, but not in the thoracic aorta, in apoE-/- CD44-/- mice compared with apoE-/- CD44+/+ mice. However, these genes were not regulated by CD44 in the context of a C57BL/6 background, illustrating the selective impact of CD44 on gene expression in a proatherogenic environment. The patterns of differential gene expression implicate CD44 in focal adhesion formation, extracellular matrix deposition, and angiogenesis, processes critical to atherosclerosis.'] Does cD44 regulate vascular gene expression in a proatherogenic environment?