title: Effect of substrate stiffness and PDGF on the behavior of vascular smooth muscle cells: implications for atherosclerosis.
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.
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Xin Q
authors.initials: XQ
authors.lastname: Brown
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Bartolak-Suki
authors.forename: Corin
authors.initials: C
authors.lastname: Williams
authors.forename: Mathew L
authors.initials: ML
authors.lastname: Walker
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Wong
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D018929:Cell Culture Techniques / Q000295:instrumentation*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004548:Elasticity; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D000099166:Polyacrylamides