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

研究血管重塑中被动和主动力学的平衡：一种综合实验和计算方法

• 批准号: 1760906
• 负责人: Susan Lessner
• 金额: $ 42.38万
• 依托单位: University of South Carolina at Columbia
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1760906&HistoricalAwards=false
• 关键词: Investigating; Balance; Passive; Active; Mechanics

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.

身体的血管经常变化，以保持健康。这个过程称为“血管重塑”，是成人血管结构、几何形状或机械特性的长期改变。在不同的疾病中，例如高血压和动脉瘤的形成，都会发生太多和太少的重塑。除了血液对血管的作用力外，细胞还拉动血管以维持功能。 研究人员最近表明，即使血液力没有改变，细胞也会改变它们对细胞壁的拉动方式，以响应饮食和年龄。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。本项目是通过实验来检验模型的预测，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，高中学生的研究经验，以及通过项目带路向高中教师推广STEM科目。 血管重构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塑的理论和计算方法经常受到缺乏实验数据的影响，无法定量描述活性生物学对重塑的贡献，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，这种不足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。这项工作可能具有变革性，能够识别和表征与年龄相关的血管重塑的新机制，独立于血流动力学变化，并提供理论和计算框架，以预测广泛的重塑结果，包括胶原纤维的重新定向及其对血管生物力学的影响。主动脉重塑的时间过程将根据血管几何形状、组成和胶原纤维方向的变化来表征。 将通过测量血压和体积流速来跟踪血液动力学对重塑的贡献。一氧化氮合酶3蛋白表达和主动脉节段的一氧化氮产生将被用作内皮功能的测量。研究人员a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，以解释在没有显著血液动力学变化的情况下，平滑肌细胞收缩收缩张力的变化驱动血管重塑的过程。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值进行评估来支持和更广泛的影响审查标准。

项目成果

The Effect of Endothelial Dysfunction on Aortic Mechanics and Extracellular Matrix Microstructure during Age-related Vascular Remodeling

年龄相关血管重塑过程中内皮功能障碍对主动脉力学和细胞外基质微结构的影响

• 发表时间: 2021
• 期刊: and Biotransport Conference (SB3C
• 作者: Rodgers, J;Shazly, T;Eberth, JF;Lessner, SM
• 通讯作者: Lessner, SM

Age-Related Collagen Remodeling Occurs in the Absence of Hypertension in Aortas of NOS3 Heterozygous Mice

NOS3 杂合子小鼠主动脉在不存在高血压的情况下发生与年龄相关的胶原重塑

• 发表时间: 2020
• 期刊: and Biotransport Conference (SB3C
• 作者: Du, Liya;Azar, Dara;Eliadorani, Dorsa;Shazly, Tarek;Lessner, Susan M.
• 通讯作者: Lessner, Susan M.

Special Issue on Advances in Cardiovascular Biomechanics

心血管生物力学进展特刊

• DOI: 10.1007/s11340-020-00683-5
• 发表时间: 2021
• 期刊: Experimental Mechanics
• 影响因子: 2.4
• 作者: Wenk, J. F.;Lessner, S. M.
• 通讯作者: Lessner, S. M.

Diet alters age-related remodeling of aortic collagen in mice susceptible to atherosclerosis

饮食改变易患动脉粥样硬化的小鼠与年龄相关的主动脉胶原蛋白重塑

• DOI: 10.1152/ajpheart.00420.2020
• 发表时间: 2021
• 期刊: American Journal of Physiology-Heart and Circulatory Physiology
• 影响因子: 4.8
• 作者: Watson, Shana R.;Cooper, Kara M.;Liu, Piaomu;Gharraee, Nazli;Du, Liya;Han, Savannah M.;Peña, Edsel A.;Sutton, Michael A.;Eberth, John F.;Lessner, Susan M.
• 通讯作者: Lessner, Susan M.

Impact of Endothelial Dysfunction on Hemodynamics and Collagen Fiber Orientation During Age-related Vascular Remodeling

年龄相关血管重塑过程中内皮功能障碍对血流动力学和胶原纤维取向的影响

• 发表时间: 2020
• 期刊: Proceedings of the 2020 SEM Annual Conference & Exposition on Experimental and Applied Mechanics
• 作者: Azar, D;Eliadorani, D;Shazly, T;Lessner, SM
• 通讯作者: Lessner, SM