Biomechanical Mechanisms of Artery Tortuosity

描述（由申请人提供）：这是一份针对PA-07-279生物工程研究资助（R01）的重新提交申请，该资助支持基础和应用多学科研究，使用综合系统方法解决重要的生物学、生物工程或医学研究问题。目标问题：当正常直的动脉出现异常弯曲和扭曲的路径时，就会发生动脉扭曲。动脉扭曲是人类常见的血管造影结果，发生在多种动脉中，从主动脉到毛细血管，从大脑到冠状动脉，从颈动脉到股动脉。闭塞性外周血管疾病患者常出现弯曲的“螺旋形”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均与动脉扭曲的高风险相关，而扭曲被认为是动脉粥样硬化和高血压发展的前兆。然而，动脉扭曲的潜在病因和生物力学机制尚不清楚。本研究的目的是通过研究血管血流动力学、屈曲和血管壁重塑之间的相互作用来确定动脉扭曲的生物力学机制。我们的中心假设是脉压升高或动脉壁减弱引发动脉屈曲，然后刺激不对称的壁重塑，加剧屈曲并逐渐导致动脉扭曲。两个具体目的是确定哪种类型的血流、机械应力和管壁性质变化引发动脉屈曲，以及屈曲如何影响动脉血流和管壁应力，以及导致动脉壁扭曲的相关适应性。方法：采用基于生物力学的模型和脉动流条件下的实验测试来研究动脉屈曲。我们将在猪颈动脉中采用弹性蛋白酶和胶原酶处理来降解特定的基质成分，以评估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检测屈曲动脉的血流、壁应力和动脉壁重塑。结果：本研究将建立动脉动态屈曲的数学和实验模型，以确定机械应力、动脉屈曲和管壁重塑之间关系的机制。益处：这些研究获得的新知识将为开发针对力学因素的预防和治疗动脉扭曲的新技术提供指导，并拓宽我们对血管生物力学的认识。

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.