BIOMECHANICAL FACTORS IN CONGENITAL VASCULAR DISEASE

先天性血管疾病的生物力学因素

• 批准号: 8774744
• 负责人: Jessica Wagenseil
• 金额: $ 33.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-13 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774744
• 关键词: BIOMECHANICAL; FACTORS; CONGENITAL; VASCULAR; DISEASE

DESCRIPTION (provided by applicant): Coarctation of the aorta (COA) is the most common congenital vascular defect. It is characterized by local narrowing of the aorta and treatment is recommended by 5 years of age. Supravalvular aortic stenosis (SVAS) is a less common congenital defect that is also characterized by local aortic narrowing. About 60% of infants diagnosed with SVAS require surgical intervention to improve heart function. Complications of COA and SVAS treatment include operative mortality, aneurysms and recoarctation requiring reoperation. In both COA and SVAS, elastic fiber fragmentation suggests that elasticity and mechanical properties of the wall may be important for disease pathology. The mechanical properties of the wall and the hemodynamic forces, blood pressure and blood flow, change significantly in late embryonic development when the arterial narrowing occurs. The proposed research will test the hypothesize that arterial narrowing is caused by altered smooth muscle cell (SMC) phenotype in response to changes in the mechanical environment during late embryonic development. The proposed research will also determine if arterial narrowing can be prevented by changing the mechanical environment during targeted developmental periods through alterations in arterial elasticity or reduced blood pressure. The hypothesis will be tested using genetically-modified mice and pharmaceutical treatments. Three mouse models with reduced arterial elasticity caused by knockouts of different proteins, elastin (Eln), fibulin-4 (Fbln4) and lysyl oxidase (Lox) will be used. Elastin is the primary component of elastic fibers in the arterial wall; fibulin-4 is necessary for proper assembly of the elastic fibers; and lysyl oxidse crosslinks the soluble form of elastin into its mechanically functional form. All three mouse lines are perinatal lethal and show local aortic narrowing, but the mechanical environment has not been characterized. Two conditional mouse lines that turn elastin on or off during late embryonic development will also be used to determine if changing the arterial elasticity minimizes, prevents or delays narrowing. Lastly, established anti- hypertensive drugs will be used to reduce blood pressure during late embryonic development and determine if reducing the hemodynamic stress on the SMCs minimizes, prevents or delays arterial narrowing. In all cases, blood pressure, blood flow and arterial mechanical properties will be measured to quantify the mechanical environment. Ultrastructural studies and targeted gene array analysis will determine how the mechanical environment affects the extracellular matrix (ECM) and SMC phenotype. These studies will be important for identifying the mechanical and genetic pathways that lead to arterial narrowing in diseases such as COA and SVAS and will test preventative treatments.

描述(申请人提供)：主动脉缩窄(COA)是最常见的先天性血管缺陷。它的特点是主动脉局部狭窄，建议在5岁前进行治疗。主动脉瓣上狭窄(SVAS)是一种少见的先天性缺陷，其特征也是局部的主动脉狭窄。约60%被诊断为SVAS的婴儿需要手术干预以改善心脏功能。COA和SVAS治疗的并发症包括手术死亡率、动脉瘤和需要再次手术的再狭窄。在COA和SVAS中，弹性纤维碎裂提示壁的弹性和机械特性可能在疾病病理中起重要作用。在胚胎发育后期，当动脉狭窄时，管壁的力学性质以及血流动力、血压和血流量都会发生显著变化。这项拟议的研究将检验这一假设，即动脉狭窄是由于胚胎发育后期机械环境的变化而改变的平滑肌细胞(SMC)表型引起的。这项拟议的研究还将确定，是否可以通过改变动脉弹性或降低血压来改变目标发育期的机械环境，从而防止动脉狭窄。这一假设将得到检验。 使用转基因小鼠和药物治疗。将使用三种因不同蛋白质(弹性蛋白(ELN)、纤维蛋白-4(Fbln4)和赖氨酰氧化酶(Lox)基因敲除而导致动脉弹性降低的小鼠模型。弹性蛋白是弹力纤维的主要成分 动脉壁；纤维蛋白-4是弹性纤维正确组装所必需的；赖氨酰氧化使可溶形式的弹性蛋白交联成机械功能形式。所有三个鼠标品系 都是围产期致命的，并显示局部主动脉狭窄，但机械环境尚未确定。在胚胎发育后期打开或关闭弹性蛋白的两个有条件的小鼠品系也将被用来确定改变动脉弹性是否会最小化、防止或延缓狭窄。最后，现有的抗高血压药物将用于在胚胎发育后期降低血压，并确定减少对SMC的血流动力学压力是否可以最大限度地减少、防止或延缓动脉狭窄。在所有情况下，都将测量血压、血流量和动脉机械特性，以量化机械环境。超微结构研究和靶向基因阵列分析将确定机械环境如何影响细胞外基质(ECM)和SMC表型。这些研究对于确定导致动脉硬化的机械和遗传途径将是重要的。 缩小COA和SVAS等疾病的范围，并将测试预防性治疗。