Biomechanical Mechanisms of Artery Tortuosity

描述(由申请人提供)：这是对PA-07-279生物工程研究基金(R01)的响应申请的重新提交，该基金支持基础和应用多学科研究，使用综合的系统方法解决重要的生物、生物工程或医学研究问题。有针对性的问题：当正常笔直的动脉走不正常的弯曲和曲折的路径时，就会发生动脉弯曲。动脉弯曲是人类常见的血管造影表现，可见于多种动脉，从主动脉到毛细血管，从脑动脉到冠状动脉，从颈动脉到股动脉。闭塞性外周血管疾病患者常出现迂曲的“开塞钻”侧支动脉。临床研究表明，高血压、衰老、动脉粥样硬化和罕见的基因突变都与动脉弯曲的风险更高相关，而弯曲被认为加速了动脉粥样硬化和高血压的发展。然而，动脉弯曲的潜在病因和生物力学机制仍不清楚。本研究的目的是通过研究血管血流动力学、屈曲和管壁重塑之间的相互作用来确定动脉弯曲的生物力学机制。我们的中心假设是，脉动压升高或动脉壁变弱会引发动脉屈曲，继而刺激不对称的管壁重构，从而加剧屈曲并逐渐导致动脉曲折。两个具体目标是确定引发动脉屈曲的血流、机械应力和壁属性的类型变化，以及屈曲如何影响动脉血流和壁应力，以及导致动脉曲折的相关动脉壁适应。方法：在脉动流条件下，采用基于生物力学的建模和实验测试来检查动脉的屈曲。在猪颈动脉中，将使用弹性酶和胶原酶处理来降解特定的基质成分，以评估管壁基质降解对动脉屈曲的影响。我们将使用一种独特的体外器官培养系统结合计算模型来研究弯曲动脉中的血流、壁应力和动脉壁重建。结果：本研究将建立动脉动态屈曲的数学和实验模型，以确定定义机械应力、动脉屈曲和管壁重塑之间关系的机制。优点：从这些研究中获得的新知识将为开发针对机械因素的预防和治疗动脉弯曲的新技术提供指导，并拓宽我们对血管生物力学的认识。 公共卫生相关性： 当正常笔直的动脉走曲折的路径时，就会发生动脉弯曲，这会损害正常的血流，导致许多症状。曲折通常与高血压、衰老和动脉粥样硬化有关。曲折的“开塞钻”侧支动脉在外周动脉疾病患者中很常见。机械因素在动脉曲折中起着重要作用。了解曲度产生和发展的生物力学机制，将揭示曲度在血管疾病中的作用，有助于对血管疾病有新的认识，并为开发新的治疗方法奠定基础。

DESCRIPTION (provided by applicant): This is a resubmission of an application in response to PA-07-279 Bioengineering Research Grant (R01), which supports basic and applied multi-disciplinary research that addresses important biological, bioengineering or medical research problems using an integrative, systems approach. Targeted Problem: Artery tortuosity occurs when normally straight arteries take an abnormal curved and tortuous path. Tortuous arteries are common angiographic findings in humans and occur in a multitude of arteries, from aorta to capillary, cerebral to coronary arteries, and carotid to femoral arteries. Tortuous "corkscrew" collateral arteries frequently occur in patients with occlusive peripheral vascular disease. Clinical studies suggest that high blood pressure, aging, atherosclerosis, and rare genetic mutations are each associated with higher risks of artery tortuosity, and tortuosity is believed to precipitate the development of atherosclerosis and hypertension. However, the underlying etiology and biomechanical mechanism of artery tortuosity remain unclear. The objective of this study is to determine the biomechanical mechanisms of artery tortuosity by investigating the interactions between vascular hemodynamics, buckling, and wall remodeling. Our central hypothesis is that elevated pulsatile pressure or weakened arterial wall initiates arterial buckling which then stimulates asymmetric wall remodeling that exacerbate buckling and gradually leads to arterial tortuosity. The two specific aims are to determine what types of blood flow, mechanical stress, and wall property changes initiate artery buckling and how buckling affects arterial blood flow and wall stress, as well as the associated adaptation of the arterial wall that leads to tortuosity. Methods: Artery buckling will be examined using biomechanics-based modeling and experimental tests under pulsatile flow conditions. The effect of wall matrix degradation on artery buckling will be evaluated in porcine carotid arteries using elastase and collagenase treatments to degrade specific matrix components. The blood flow, wall stress, and arterial wall remodeling in buckled arteries will be examined using a unique ex vivo organ culture system combined with computational modeling. Outcomes: This study will establish mathematical and experimental models of artery dynamic buckling to determine the mechanisms that define the relationship among mechanical stress, artery buckling, and wall remodeling. Benefits: The new knowledge obtained from these studies will provide guidance in developing new techniques for the prevention and treatment artery tortuosity by targeting the mechanical factors and broaden our knowledge of vascular biomechanics. PUBLIC HEALTH RELEVANCE: Artery tortuosity occurs when the normally straight arteries take a tortuous path, which impairs normal blood flow causes many symptoms. Tortuosity is often associated with hypertension, aging, and atherosclerosis. Tortuous "corkscrew" collateral arteries are common in patients with peripheral artery disease. Mechanical factors play a significant role in artery tortuosity. Understanding the biomechanical mechanisms how tortuosity initiates and develop will reveal its role in vascular disease and lead to new understanding of vascular disease and set a basis for development of new treatment.