Abstract The physical and biochemical components of the arterial microenvironment, such as matrix stiffness and elasticity, and the portfolio of insoluble adhesive proteins, are altered during atherosclerosis. Coincident with these extracellular changes, smooth muscle cells (SMCs) undergo phenotypic dedifferentiation, wherein they alter gene transcription, become motile, and proliferate. Chemical and physical cues from the growing plaque, as well as the remodeled matrix, trigger the invasion of SMCs into the arterial intimal wall via activation of integrin- and growth factor-initiated signaling networks. Once there, these pathophysiological SMCs proliferate and deposit proteins, participating in disease progression. This process is well documented and appreciated in vivo, and many lab, including our own, have sought to make a connection between these physical matrix changes and SMC patho-physiology. However, there remains a critical gap in the field, as existing model systems have likely been still far to simple to capture the complexity of this in vivo phenomenon. In response to this critical gap, we propose to adapt and improve our model system that has independent control over static mechanical properties (elastic modulus), dynamic mechanical forces (rate and magnitude of stretch), and integrin binding. This is a high-throughput device that will allow for rapid, simultaneous profiling of hundreds of individual cells as a function of several different vessel property conditions. As proof of concept toward possible clinical applications, we will quantify SMC response to cardiovascular drugs while subjected to physiological stiffness, integrin binding, and stretch. We propose this system could transform the field's view of how matrix mechanics in a diseased vessel wall alter SMC behavior, ultimately leading to new therapeutic approaches targeting SMC mechanosensing.
NIH ExPorter
NIH ExPorter