title: Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways.
abstract: 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) after balloon catheter injury. 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 gene expression following a change in cyclic stress from 10% to 20% (28 h: 181 +/- 1%; P < 0.05). Mechanical stress induced a late decrease in cell-associated S4 protein levels (24 h: 70 +/- 6%; P < 0.05), with an associated increase in S4 shedding (24 h: 537 +/- 109%; P < 0.05). To examine the role of MAP kinases, cells were treated with U-0126 (ERK1/2 inhibitor), SB-203580 (p38 inhibitor), or JNKI I (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 (4-fold reduction; P < 0.05) signaling. Given the varied functions of S4, stress-induced effects on SMC S4 expression and shedding 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.
authors.affiliation: Department of Surgery and Biomedical Engineering, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA.
authors.forename: Matheau A
authors.initials: MA
authors.lastname: Julien
authors.forename: Peiyi
authors.initials: P
authors.lastname: Wang
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Haller
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Chaikof
mesh_terms: D001011:Aorta; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism*; D013314:Stress, Mechanical; D053671:Syndecan-4 / Q000378:metabolism*
chemical_list: D053671:Syndecan-4; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases