Empirically Determined Growth Laws for Vascular Smooth Muscle Cell Mechano-Adaptation

可用的实验测量值与填充函数数学模型所需的测量值之间经常存在脱节。该项目将创建一套紧密结合的实验和模型，以预测动脉如何响应内部血流负荷而发生变化。这项工作的结果将是预测动脉系统在生长过程中如何发展所需的框架。结果将被纳入PI的研究生水平组织力学课程。此外，PI的本科生物力学课程将与现有的针对Harambee小学二年级学生的扩展计划相结合，在该计划中，年轻学生将学习解决问题的工程方法的一些基本原理。传统的机械适应模型采用现象生长规律，将动脉组织或血管平滑肌细胞（VSMC）应激与血管重构联系起来。这种方法可以提供重要的定性见解，但为了使理论具有预测性，它需要更好地与血管生理学联系起来。对VSMC细胞生物学的研究表明，通常使用的简单生长规律不太可能普遍描述VSMC的机械适应。例如，VSMCs很容易在两种表型（收缩型和合成型）之间切换，具有明显不同的行为。这种转换在适应和不适应的重塑过程中尤为明显，这表明它是机械适应过程中的关键步骤。此外，血管功能障碍，如高血压或动脉粥样硬化，可导致VSMCs周围机械环境的长期变化。虽然在力学适应模型中经常包含矩阵力学的变化，但力学变化对VSMC函数的影响却没有被考虑在内。主要研究人员假设表型转换在血管平滑肌机械适应中起着重要的可测量作用，并且表型和机械适应动力学都受到细胞外力学特性的影响。他们将采用新颖的体外实验来直接测量VSMC的机械适应性，并利用这些测量结果来开发更深入的理论，用于动脉力学模型。

There is often a disconnect between the available experimental measurements and those needed to populate functional mathematical models. This project will create a tightly integrated set of experiments and models to predict how arteries change in response to the internal loading of blood flow. The results of this work will be the framework needed to predict how the arterial system develops during growth. The results will be incorporated into the PI's graduate-level Tissue Mechanics course. In addition, the PI's undergraduate-level Biomechanics course will be integrated with an existing outreach program to 2nd graders at Harambee Elementary School where the young students learn some basic fundamentals of the engineering approaches to problem solving.Traditionally, mechano-adaptation models have employed phenomenological growth laws that connect arterial tissue or vascular smooth muscle cell (VSMC) stress with vessel remodeling. This approach can give important qualitative insight, but for the theory to be predictive, it needs to be better connected to vessel physiology. An examination of VSMC cell biology suggests that the simple growth laws commonly used are unlikely to universally describe VSMC mechano-adaptation. For example, VSMCs readily switch between two phenotypes (contractile and synthetic) with markedly different behaviors. This switching is particularly pronounced during remodeling, both adaptive and maladaptive, suggesting that it is a key step in the mechano-adaptation process. Additionally, vascular dysfunctions, such as hypertension or atherosclerosis, can lead to long-term changes in the mechanical environment surrounding VSMCs. While the changes in matrix mechanics are often included in mechano-adaptation models, the effect of the change in mechanics on VSMC function is not. The principal investigators hypothesize that phenotype switching plays an important measurable role in vascular smooth muscle mechano-adaptation, and that both phenotype and mecahno-adaptation dynamics are influenced by extracellular mechanical properties. They will employ novel in vitro assays to directly measure VSMC mechano-adaptation and use these measurements to develop more in-depth theory for use in models of artery mechanics.