Syndecan-4 (S4) belongs to a family of transmembrane proteoglycans, acts as a coreceptor for growth factor binding, as well as cell-matrix and cell-cell interactions, and is induced in neointimal smooth muscle cells (SMCs) following balloon catheter injury. In this report, we investigated S4 expression in SMCs in response to several force profiles and the role of MAP kinase signaling pathways in regulating these responses. S4 mRNA expression increased in response to 5% and 10% cyclic strain (4 h: 200 ± 34% and 182 ± 17%, respectively, p < 0.05) before returning to basal levels by 24 h. Notably, the SMC mechanosensor mechanism was reset after an initial 24 h "preconditioning" period, as evident by an increase in S4 expression following a change in cyclic stress from 10% to 20% (28 h: 181 ± 1%, p < 0.05). Stress induced a late decrease in cell-associated S4 protein (24 h: 70 ± 6%, p < 0.05), with an associated increase in S4 shedding (24 h: 537 ± 109%, p < 0.05). In order to examine the role of MAP kinases, cells were treated with U0126 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), or JNKI1 (JNK/SAPK inhibitor). Late reduction in cell-associated S4 levels was attributed to ERK1/2 and p38 signaling. In contrast, accelerated S4 shedding required both ERK1/2 (5-fold reduction in accelerated shedding, p < 0.05) and JNK/SAPK signaling (4-fold reduction, p < 0.05). Given the varied functions of S4, stress induced effects on SMC S4 expression and shedding may represent an additional component of the pro-inflammatory, growth-stimulating pathways that are activated in response to changes in the mechanical microenvironment of the vascular wall.