Mechanical Strain-Mediated Syndecan Regulation and Its Effects on Adhesion of Vascular Smooth Muscle Cells

An injured vascular system has a substantial impact on an individuals overall health, and an understanding of the mechanisms that underlie blood vessel pathophysiology is required for the development of rational and effective treatment strategies. The phenotypic modulation of smooth muscle cells (SMC) during vascular injury, characterized by altered adhesion, migration and synthetic behavior, plays an important role in the eventual outcome. Specifically, the ability of SMCs to adhere to and remodel their extracellular environment via regulation of the syndecan class of cell adhesion molecules dictates the response of the vascular wall to local injury. The effect of in vitro syndecan-4 regulation on SMC adhesion was investigated through the use of a glass microsphere centrifugation assay, and an antisense-mediated reduction in gene expression was found to correlate with decreased adhesive strength. Regulation of syndecan-1, syndecan-2, and syndecan-4 gene expression was observed experimentally by mechanical strain of SMCs. Using real-time polymerase chain reaction (PCR), the kinetics of both static and cyclic mechanical strain were found to modify the gene expression in a time and strain magnitude-dependent manner unique to each syndecan. In particular, the responses of syndecan-4 were acute, but transient, while the evolution of syndecan-1 and syndecan-2 regulation was delayed by comparison. Mechanical strain also modulated syndecan-4 protein expression and ectodomain shedding, as measured by Western immunoblotting, and this effect was found, through selective inhibition, to be at least in part dependent on mitogen-activated protein (MAP) kinase signaling. In particular, intact extracellular signal-regulated MAP kinase (ERK) 1/2 and c-Jun NH2-terminal kinase / stress-activated protein kinase (JNK/SAPK) signaling pathways were found to be required for the observed strain-induced shedding. These findings offer a better understanding of syndecan function in response to mechanical strain and suggest potential new mechanisms by which physical forces may modulate vascular SMC behavior and regulation during normal physiology, pathologic conditions, and engineered arterial substitute development.

Department dc:contributor.department

Biomedical Engineering

Grantor dc:publisher

Georgia Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• Julien, Mathéau A.

Advisors dc:contributor.advisor

• Chaikof, Elliot L.
• García, Andrés J.

Committee members dc:contributor.committeemember

• Anew P. Kowalczyk
• Taylor, W. Robert
• Galis, Zorina S.

• Vascular graft
• Mitogen activated protein kinase
• Tissue engineering
• Ectodomain shedding
• Cell adhesion
• Smooth muscle
• Cyclic strain
• Cyclic stress
• Biomechanics
• Syndecan
• Heparan sulfate proteoglycan

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/1853/7007

OAI identifier oai:identifier

oai:repository.gatech.edu:1853/7007