Rapid micro-patterned stretching platform to study cell behaviors during atherosclerosis

摘要 动脉微环境的物理和生化成分，如基质僵硬和 在动脉粥样硬化过程中，弹性和不溶性黏附蛋白的组合会发生变化。与…重合 这些细胞外变化，平滑肌细胞(SMC)经历表型去分化，其中它们 改变基因转录，变得能动，并增殖。从不断生长的斑块中得到的化学和物理线索， 以及重塑的基质，通过激活血管内膜，触发SMC侵入动脉内膜 整合素和生长因子启动的信号网络。一旦到了那里，这些病理生理的SMC就会增殖 和沉积蛋白质，参与疾病的发展。这一过程得到了很好的记录，并在 VIVO和许多实验室，包括我们自己，已经试图在这些物理基质之间建立联系 改变与SMC的病理生理。然而，与现有模式一样，这一领域仍然存在严重差距 要捕捉到这种活体现象的复杂性，系统可能仍然远未达到简单的程度。 为了应对这一关键差距，我们建议调整和改进我们的模型系统，使其具有独立的 控制静态机械性能(弹性模数)、动态机械力(速率和大小 拉伸)和整合素结合。这是一种高通量设备，将允许快速、同步地分析 数百个单独的细胞作为几个不同的血管属性条件的函数。作为概念的证明 对于可能的临床应用，我们将量化SMC对心血管药物的反应 生理僵硬、整合素结合和拉伸。我们认为，这一系统可以改变该领域对 病变血管壁中的基质力学如何改变SMC的行为，最终导致新的治疗方法 针对SMC机械传感的方法。

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.