Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry.
Smooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin-binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble factors are major drivers of several critical SMC behaviors, such as motility, proliferation, invasion, and differentiation marker expression, and these factors modulated the effect of stiffness on proliferation and migration. Overall, modulus only modestly affected behaviors other than proliferation, relative to integrin binding and soluble factors. Surprisingly, pathological behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conflict with previous studies on substrates coupled with single extracellular matrix (ECM) proteins. A high-throughput bead-based ELISA approach and inhibitor studies revealed that differentiation marker expression is mediated chieflyviafocal adhesion kinase (FAK) signaling, and we propose that integrin binding and FAK drive the transition from a migratory to a proliferative phenotype. We emphasize the importance of increasing the complexity ofin vitrotesting platforms to capture these subtleties in cell phenotypes and signaling, in order to better recapitulate important features ofin vivodisease and elucidate potential context-dependent therapeutic targets.
Department of Chemical Engineering, University of Massachusetts, 686 N. Pleasant Street, 159 Goessmann Laboratory, Amherst, MA 01003, USA.
William G
WG
Herrick
Polymer Science and Engineering Department, University of Massachusetts, Conte Polymer Research Center, 120 Governors Dr., Amherst, MA 01003, USA.
Shruti
S
Rattan
Department of Chemical Engineering, University of Massachusetts, 686 N. Pleasant Street, 159 Goessmann Laboratory, Amherst, MA 01003, USA.
Thuy V
TV
Nguyen
Department of Chemical Engineering, University of Massachusetts, 686 N. Pleasant Street, 159 Goessmann Laboratory, Amherst, MA 01003, USA.
Michael S
MS
Grunwald
Department of Materials Engineering, Purdue University, West Lafayette, USA.
Christopher W
CW
Barney
Polymer Science and Engineering Department, University of Massachusetts, Conte Polymer Research Center, 120 Governors Dr., Amherst, MA 01003, USA.
Alfred J
AJ
Crosby
Department of Chemical Engineering, University of Massachusetts, 686 N. Pleasant Street, 159 Goessmann Laboratory, Amherst, MA 01003, USA.
Shelly R
SR
Peyton
Atherosclerosis; Extracellular matrix; Hydrogel; Mechanobiology; Poly(ethylene glycol)