Mechanical Stress Regulates Syndecan-4 Expression and Redistribution in Vascular Smooth Muscle Cells

Abstract

Abstract-Syndecan-4 is a unique membrane-associated heparan sulfate proteoglycan that colocalizes with integrin heterodimers in focal adhesion complexes. Because focal adhesions serve as a putative mechanotransduction system, we postulated that physical forces that are sensed by focal adhesions may regulate the expression and intracellular distribution of syndecan-4 and thereby modulate cell movement and orientation. In this report, syndecan-4 was identified as a transcriptionally regulated, immediate-early gene in response to the application of oscillatory stress. This fluctuation was associated with coordinate changes in the concentration and compartmentalization of syndecan-4 proteins. Specifically, syndecan-4 was lost from the dorsal aspect of the cell membrane and translocated from its intracellular pool to the ventral cell surface. Dissociation of syndecan-4 and vinculin from focal adhesions may contribute to promoting cell motility, because overexpression of syndecan-4, in part, blocked this dissociation and also retarded mechanical stretch-induced cell migration. These studies suggest that mechanical stress induces cell locomotion, in part, by the dynamic regulation of syndecan-4 expression and relocation. Key Words: restenosis Ⅲ hypertension Ⅲ atherosclerosis Ⅲ heparan sulfate Ⅲ syndecan V ascular smooth muscle cells (SMCs) are subjected to a dynamic, mechanical environment modulated by pulsatile pressure and oscillatory shear forces. Although these forces are important regulators of normal cell function, under certain conditions they may contribute to the development of a pathological state. For example, hypertension, which increases transmural stresses due to mechanical distension of the arterial wall, leads to vascular wall hypertrophy and is an independent risk factor for the development of atherosclerosis. 1 Strong correlations have also been noted between regions of elevated wall stresses and the propensity for rupture of either an atherosclerotic plaque or an aortic aneurysm. 2,3 Likewise, the restenosis response that often follows balloon angioplasty may be due, in part, to the extreme vessel wall strains that are associated with this mechanical intervention. 4 Although these observations support the notion that wall stress is a potent stimulus for pathophysiological adaptations of the vessel wall, the underlying molecular and cellular mechanisms that eventually lead to a pathological end point remain largely undefined.Syndecan-4 is a cell surface heparan sulfate proteoglycan (HSPG) widely expressed in tissues derived from ectoderm, mesenchyme, and endoderm in a position-, time-, and development-dependent manner. 5 The ectodomain of syndecan-4 bears 3 distinct heparan sulfate (HS) chains that are capable of binding a variety of ligands that modulate events relevant to acute tissue repair and chronic injury responses, including cell migration and proliferation, cellsubstrate interactions, and matrix remodeling. 6,7 In this regard, syndecan-4 serves as a coreceptor for a variety of soluble ligands...

Defining the role of syndecan-4 in mechanotransduction using surface-modification approaches

“…By comparing these activation levels to unstretched cells (0 min), these findings indicated that the activation is not just attachment based, but that mechanical stimulation is required. These ERK phosphorylation responses after syndecan-4-based mechanical stimulation were similar to integrin-based responses under mechanical stimulation (31). The surface strain of the PDMS substrate was an average of 10%.…”

Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways

“…Moreover, several reports have noted that an absolute reduction in these cell surface receptors, as a consequence of shedding, may alter cell responses to both soluble and insoluble heparin binding proteins. For example, we recently observed (19,20) that stress-induced loss of syndecan-4 is associated with an increase in fibroblast and vascular smooth muscle cell (SMC) movement on fibronectin.…”

“…For example, in a study of 19,083 men, pulse pressure was the strongest predictor of cardiovascular mortality (3). Since our initial investigations suggest that mechanical stress promotes syndecan shedding from vascular SMCs, we have postulated that this response may represent an additional component of the proinflammatory, growth-stimulating pathways that are activated in response to changes in the mechanical microenvironment of the vascular wall (19). Fitzgerald et al (8) previously demonstrated that extracellular signal-related kinase (ERK)1/2 activity was required for syndecan shedding induced by epidermal growth factor (EGF) and thrombin receptor activation, whereas p38 mitogen-activated protein (MAP) kinase activity was not involved.…”

Fibroblast growth factor 2 endocytosis in endothelial cells proceed via syndecan-4-dependent activation of Rac1 and a Cdc42-dependent macropinocytic pathway

“…This possibility is bolstered by observations that syndecan-4 binding to soluble (e.g. growth factors) or extracellular matrix ligand or cell exposure to mechanical stress results in its endocytosis (Li and Chaikof, 2002;Tkachenko and Simons, 2002). However, the link between syndecan-4 endocytosis and FGF2 internalization as well as molecular mechanisms of this process have not been defined.…”