Effect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: implications for atherosclerosis.

TitleEffect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: implications for atherosclerosis.
Publication TypeJournal Article
Year of Publication2010
AuthorsBrown XQ, Bartolak-Suki E, Williams C, Walker ML, Weaver VM, Wong JY
JournalJ Cell Physiol
Volume225
Issue1
Pagination115-22
Date Published2010 Oct
ISSN1097-4652
KeywordsAcrylic Resins, Animals, Atherosclerosis, Cattle, Cell Culture Techniques, Cell Movement, Cell Proliferation, Cells, Cultured, Elasticity, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Platelet-Derived Growth Factor, Receptors, Platelet-Derived Growth Factor
Abstract

Vascular disease, such as atherosclerosis, is accompanied by changes in the mechanical properties of the vessel wall. Although altered mechanics is thought to contribute to disease progression, the molecular mechanisms whereby vessel wall stiffening could promote vascular occlusive disease remain unclear. It is well known that platelet-derived growth factor (PDGF) is a major stimulus for the abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) and contributes critically to vascular disease. Here we used engineered substrates with tunable mechanical properties to explore the effect of tissue stiffness on PDGF signaling in VSMCs as a potential mechanism whereby vessel wall stiffening could promote vascular disease. We found that substrate stiffness significantly enhanced PDGFR activity and VSMC proliferation. After ligand binding, PDGFR followed distinct routes of activation in cells cultured on stiff versus soft substrates, as demonstrated by differences in its intensity and duration of activation, sensitivity to cholesterol extracting agent, and plasma membrane localization. Our results suggest that stiffening of the vessel wall could actively promote pathogenesis of vascular disease by enhancing PDGFR signaling to drive VSMC growth and survival.

DOI10.1002/jcp.22202
Alternate JournalJ. Cell. Physiol.
PubMed ID20648629
PubMed Central IDPMC2920297
Grant ListR01 CA138818 / CA / NCI NIH HHS / United States
R01 HL072900 / HL / NHLBI NIH HHS / United States
R01 HL072900-07 / HL / NHLBI NIH HHS / United States
R01 HL072900-08 / HL / NHLBI NIH HHS / United States