Published online before print October 2, 2008

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(American Journal of Pathology. 2008;173:1577-1588.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080042

Regulation of the Atheroma-Enriched Protein, SPRR3, in Vascular Smooth Muscle Cells through Cyclic Strain is Dependent on Integrin 1β1/Collagen Interaction

Amy L. Pyle^*, James B. Atkinson^*||, Ambra Pozzi, Jeff Reese, Beate Eckes^¶, Jeffrey M. Davidson^*||, Dan L. Crimmins^** and Pampee P. Young^*||

From the Departments of Pathology,^* Internal Medicine, Cancer Biology, and Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; the Department of Dermatology,^¶ University of Cologne, Cologne, Germany; The Department of Veterans Affairs Medical Center|| , Nashville, Tennessee; and the Department of Pathology and Immunology,^** Washington University School of Medicine, St. Louis, Missouri

Atherosclerotic plaques express high levels of small proline-rich repeat protein (SPRR3), a previously characterized component of the cornified cell envelope of stratified epithelia, where it is believed to play a role in cellular adaptation to biomechanical stress. We investigated the physiological signals and underlying mechanism(s) that regulate atheroma-enriched SPRR3 expression in vascular smooth muscle cells (VSMCs). We showed that SPRR3 is expressed by VSMCs in both human and mouse atheromas. In cultured arterial VSMCs, mechanical cyclic strain, but neither shear stress nor lipid loading induced SPRR3 expression. Furthermore, this upregulation of SPRR3 expression was dependent on VSMC adherence to type I collagen. To link the mechanoregulation of SPRR3 to specific collagen/integrin interactions, we used blocking antibodies against either integrin 1 or 2 subunits and VSMCs from mice that lack specific collagen receptors. Our results showed a dependence on the 1β1 integrin for SPRR3 expression induced by cyclic strain. Furthermore, we showed that integrin 1 but not 2 subunits were expressed on VSMCs within mouse lesions but not in normal arteries. Therefore, we identified the enrichment of the mechanical strain-regulated protein SPRR3 in VSMCs of both human and mouse atherosclerotic lesions whose expression is dependent on the collagen-binding integrin 1β1 on VSMCs. These data suggest that SPRR3 may play a role in VSMC adaptation to local biomechanical stress within the plaque microenvironment.