Investigating the Balance of Passive and Active Mechanics in Vascular Remodeling: An Integrated Experimental and Computational Approach

为了保持健康，人体的血管经常会发生变化。这一过程被称为“血管重塑”，是成人血管结构、几何形状或机械性能的长期变化。在不同的疾病中都会发生过多或过少的重塑，例如高血压和动脉瘤的形成。除了血液对血管的作用力外，细胞还会拉动血管以维持功能。研究人员最近发现，即使在血液力不变的情况下，细胞也会随着饮食和年龄的变化而改变它们拉动细胞壁的方式。由细胞引起的血管壁变化的实验结果成功地模拟了正常小鼠，并预测了在血管中缺少重要化学信息的实验小鼠(一氧化氮缺乏小鼠)的血管将如何变化。本项目是对模型预测进行实验检验，以确定模型是否正确。该项目的教育和推广方面包括生物力学和机械生物学的本科生和研究生培训、课程开发、高中生的研究经验，以及通过Project Lead Way向高中教师推广STEM科目。血管重塑是常见血管疾病的重要组成部分。该研究项目将提高预测疾病进展和改善公众健康的能力。使用连续介质力学分析血管重构的理论和计算方法经常受到缺乏实验数据的限制，无法提供对重构的积极生物学贡献的定量描述，例如激活的平滑肌细胞的贡献。通过提供一个创新的、紧密集成的框架，结合实验和数学分析，这一缺陷将在与年龄相关的血管重塑及其对内皮功能障碍的反应的背景下得到解决。这项工作具有潜在的变革性，因为它能够识别和表征一种独立于血流动力学变化的与年龄相关的血管重塑的新机制，并提供一个理论和计算框架，能够预测广泛的重塑结果，包括胶原纤维的重定向，以及它们对血管生物力学的影响。主动脉重塑的时间进程将通过血管几何形状、成分和胶原纤维取向的变化来表征。血流动力学对重塑的贡献将通过测量血压和体积流速来跟踪。一氧化氮合酶3蛋白的表达和主动脉段一氧化氮的产生将被用作内皮功能的衡量标准。研究人员将开发并独立验证一个数学框架，该框架结合了动脉组织的被动和主动本构模型，以解释在没有明显血流动力学变化的情况下，平滑肌细胞收缩张力的变化驱动血管重构的过程。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The blood vessels of the body often change in order to maintain health. This process, called "vascular remodeling" is a long-lasting alteration in structure, geometry, or mechanical properties of adult blood vessels. Both too much and too little remodeling occur in different diseases, for example, in high blood pressure and in the formation of an aneurysm. In addition to the forces of blood on the vessels, the cells also pull on the vessel to maintain function. The investigators recently showed that the cells change how they pull on the cell walls in response to diet and age even when the blood forces aren't changed. The experimental results of changes in the vessels walls caused by the cells was successfully modeled for normal mice and makes a prediction on how the blood vessels will change in experimental mice missing an important chemical message in the blood vessels (nitric oxide deficient mice). This project is to experimentally test the model prediction to determine whether the model is correct. The educational and outreach aspects of the project include undergraduate and graduate training in biomechanics and mechanobiology, course development, research experiences for high school students, and outreach to high school teachers in STEM subjects through Project Lead the Way. Blood vessel remodeling is a key part of common vascular diseases. The research project will improve the ability to predict disease progression and improve public health.Theoretical and computational approaches to analyze vascular remodeling using continuum mechanics have often suffered from a lack of experimental data to provide quantitative descriptions of active biological contributions to remodeling, such as the contribution of activated smooth muscle cells. By providing an innovative, tightly integrated framework incorporating both experimental and mathematical analysis, this shortfall will be addressed in the context of age-related vascular remodeling and its response to endothelial dysfunction. This work is potentially transformative in its ability to identify and characterize a novel mechanism of age-related vascular remodeling independent of hemodynamic changes, and to provide a theoretical and computational framework with the power to predict a wide spectrum of remodeling outcomes, including reorientation of collagen fibers, and their effects on vascular biomechanics. The time course of aortic remodeling will be characterized in terms of changes in vessel geometry, composition, and collagen fiber orientation. Hemodynamic contributions to remodeling will be tracked by measuring blood pressures and volumetric flow rates. Nitric oxide synthase 3 protein expression and nitric oxide production by aortic segments will be used as measures of endothelial function. The researchersa will develop and independently validate a mathematical framework that incorporates a combined passive and active constitutive model of arterial tissue to explain the process by which changes in smooth muscle cell contraction contractile tone drive vascular remodeling in the absence of significant hemodynamic changes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.