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

在可用的实验测量和填充函数数学模型所需的测量之间经常存在脱节。该项目将创建一组紧密集成的实验和模型，以预测动脉如何响应血流的内部负荷而变化。这项工作的结果将是预测动脉系统在生长过程中如何发育所需的框架。 研究结果将纳入PI的研究生水平的组织力学课程。此外，PI的本科生生物力学课程将与Harambee小学二年级学生现有的推广计划相结合，在那里年轻的学生学习解决问题的工程方法的一些基本原理。传统上，机械适应模型采用了将动脉组织或血管平滑肌细胞（VSMC）应力与血管重塑联系起来的现象学生长定律。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定律不太可能普遍描述VSMC的机械适应。例如，VSMC容易在具有显著不同行为的两种表型（收缩型和合成型）之间切换。这种转换在适应性和适应不良的重塑过程中特别明显，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VSMC周围机械环境的长期变化。虽然基质力学的变化通常包括在力学适应模型中，但力学变化对VSMC功能的影响并不包括在内。 主要研究者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的作用，并且表型和机械适应动力学都受到细胞外机械特性的影响。他们将采用新的体外试验来直接测量VSMC的机械适应性，并使用这些测量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.