Regulation of the Atheroma-Enriched Protein, SPRR3, in Vascular Smooth Muscle Cells through Cyclic Strain is Dependent on Integrin α1β1/Collagen Interaction

Abstract

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 ␣1␤1 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 ␣1␤1 on VSMCs. These data suggest that SPRR3 may play a role in VSMC adaptation to local biomechanical stress within the plaque microenvironment.

Upregulation of SPRR3 Promotes Colorectal Tumorigenesis

“…Therefore, we investigated the expression of PTEN and phospho-PI3K in SPRR3-overexpressing cells, and found that these proteins were not significantly altered by SPRR3 expression (data not shown). It was recently reported that increased α1β1-integrin enhances SPRR3 expression (33), and integrin could induce AKT activation through the integrinassociated protein ILK (integrin-linked kinase) (34,35). The molecular mechanisms underlying the activation of AKT by SPRR3 are not clear, and further investigation is therefore needed to elucidate the specific mechanisms.…”

Atheromas Feel the Pressure

“…For example, expression of ␣ 1 ␤ 1 integrin within VSMCs of an atheroma alters signal transduction downstream of cyclic strain and possibly other biomechanical forces as well matrix/cell interactions differentially within the cells comprising the atheroma resulting in unique gene expression. 31 This demonstrates the need to recapitulate multiple features of the in vivo microenvironment when studying vascular biology in vitro. Not only should the cellular and ECM components be consistent with the physiological context, but the mechanical strains of the system should also be accounted for when working in vitro.…”

“…[31][32][33] However, within the context of vascular pathologies such as hypertension and atherosclerosis, certain mechanosensors are differentially regulated. For example, the angiotensin type I receptor, which has been shown to be a mechanosensor in VSMCs, is up-regulated in atherosclerosis.…”

“…35 Additionally, it has been shown that expression of integrin ␣ 1 ␤ 1 on VSMCs is limited to atheromas. 31 In the context of the atherosclerotic plaque, VSMCs are surrounded by ECM, primarily type I collagen, and to a lesser extent elastin, vitronectin, and fibronectin. 8 Cells can relate to and sense this environment through integrin-ECM interactions, thus making this interface an important focus of study.…”

“…For example, our lab and others have demonstrated expression of the type I collagen binding integrin ␣ 1 ␤ 1 by VSMCs within atheromas, and rarely by VSMCs of normal vasculature. 31,45 This is the result of the influence of the atheroma microenvironment, which is rich in various cytokines such as transforming growth factor ␤, platelet-derived growth factor, monocyte chemoattractant protein 1, and others that modulate VSMC gene expression (Figure 1). 11 The nature of this microenvironment causes biomechanical stress to differentially affect the VSMCs.…”