Biomechanical Factors in Congenital Vascular Disease

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。其特点是局部主动脉狭窄，建议在5岁前治疗。瓣上主动脉狭窄（SVAS）是一种不太常见的先天性缺陷，也以局部主动脉狭窄为特征。大约60%被诊断为SVAS的婴儿需要手术干预来改善心脏功能。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缝合。在COA和SVAS中，弹性纤维断裂表明壁的弹性和力学特性可能对疾病病理很重要。在胚胎发育后期，当动脉狭窄发生时，血管壁的力学特性和血流动力学力、血压和血流发生显著变化。拟议的研究将验证动脉狭窄是由平滑肌细胞（SMC）表型改变引起的，以响应胚胎发育后期机械环境的变化。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时期的机械环境来预防动脉狭窄。这一假设将得到检验

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. PUBLIC HEALTH RELEVANCE: The most common congenital vascular defect is coarctation of the aorta, which has a mortality rate of 75% by 45 years of age if untreated. Treatment is usually recommended before 5 years of age and treatment complications include operative mortality, recoarctation and aneurysms. The goal of the proposed research is to test the hypothesis that coarctation is caused by changes in the vascular cell phenotype when there are alterations in the mechanical environment and that coarctation can be prevented by reversing the changes in the mechanical environment.