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

经验确定的血管平滑肌细胞机械适应的生长规律

• 批准号: 1563198
• 负责人: Patrick Alford
• 金额: $ 36.67万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1563198&HistoricalAwards=false
• 关键词: Empirically; Determined; Growth; Laws; Vascular

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.

可用的实验测量与填充函数数学模型所需的测量之间经常存在脱节。该项目将创建一套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。这项工作的结果将成为预测动脉系统在生长过程中如何发育所需的框架。 研究结果将被纳入 PI 的研究生水平组织力学课程中。此外，PI 的本科生物力学课程将与 Harambee 小学二年级学生的现有推广计划相结合，年轻学生将学习解决问题的工程方法的一些基本原理。传统上，机械适应模型采用现象学方法将动脉组织或血管平滑肌细胞 (VSMC) 应激与血管重塑联系起来的生长规律。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 细胞生物学的检查表明，常用的简单生长定律不太可能普遍描述 VSMC 机械适应。例如，VSMC 很容易在行为明显不同的两种表型（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尤其明显，表明这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，可能导致 VSMC 周围机械环境的长期变化。虽然矩阵力学的变化通常包含在力学适应模型中，但力学变化对 VSMC 功能的影响却没有包含在内。 主要研究人员假设表型转换在血管平滑肌机械适应中发挥重要的可测量作用，并且表型和机械适应动力学都受到细胞外机械特性的影响。他们将采用新颖的体外测定法来直接测量 VSMC 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。