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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:886.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

CD44 Regulates Vascular Gene Expression in a Proatherogenic Environment

Liang Zhao; Jason A. Hall; Natasha Levenkova; Eric Lee; Melissa K. Middleton; Alicia M. Zukas; Daniel J. Rader; John J. Rux; Ellen Puré

From the Wistar Institute and The Ludwig Institute for Cancer Research, Philadelphia, Pa; and the Department of Medicine and the Graduate Group in Immunology, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Ellen Puré, PhD, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104. E-mail pure{at}wistar.org

Objective— To identify early changes in vascular gene expression mediated by CD44 that promote atherosclerotic disease in apolipoprotein E (apoE)–deficient (apoE–/–) mice.

Methods and Results— 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 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.

Conclusions— CD44 is an early mediator of atherogenesis by virtue of its ability to regulate vascular gene expression in response to a proatherogenic environment.

We demonstrate that CD44 is selectively upregulated and functionally activated in lesion-prone aortic arch of apoE–/– mice before lesion development. Furthermore, gene expression profiling revealed a selective impact of CD44 on vascular gene expression in response to a proatherogenic environment illustrating that CD44 is an early mediator of atherogenesis.

Key Words: CD44 • apoE • gene expression • vascular • hyaluronan • atherosclerosis

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