Biomechanical Factors in Congenital Vascular Disease

先天性血管疾病的生物力学因素

• 批准号: 8335042
• 负责人: Jessica Wagenseil
• 金额: $ 37.5万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335042
• 关键词: 5 year old; Adverse effects; Affect; Age-Years; Aneurysm; Antihypertensive Agents; Aorta; Aortic coarctation; Biomechanics; Birth; Blood Pressure; Blood Vessels; Blood flow; Cells; Congenital Abnormality; Defect; Development; Diagnosis; Disease; Distal; Elastic Fiber; Elasticity; Elastin; Embryo; Embryonic Development; Environment; Extracellular Matrix; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Human; Infant; Knock-out; Lead; Measures; Mechanics; Mouse Strains; Mus; Operative Surgical Procedures; Pathology; Pathway interactions; Perinatal; Pharmacologic Substance; Phenotype; Property; Protein-Lysine 6-Oxidase; Proteins; Repeat Surgery; Research; Signal Transduction; Site; Smooth Muscle Myocytes; Stress; Supravalvular aortic stenosis; Testing; Time; Vascular Diseases; arterial remodeling; critical period; crosslink; fibulin-4; heart function; hemodynamics; human disease; improved; mechanical behavior; mortality; mouse development; mouse model; new therapeutic target; novel; prevent; response

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.

描述（由申请人提供）：主动脉（COA）的缩合是最常见的先天性血管缺陷。它的特征是局部主动脉狭窄，并建议在5岁之前进行治疗。上主动脉狭窄（SVAS）是一个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％的被诊断为SVA的婴儿需要手术干预以改善心脏功能。 COA和SVA治疗的并发症包括手术死亡率，动脉瘤和重新调节需要重新手术。在COA和SVA中，弹性纤维碎裂表明壁的弹性和机械性能对于疾病病理可能很重要。当动脉狭窄发生时，壁和血液动力学，血压和血流的机械性能在晚期发育中发生了明显变化。拟议的研究将测试假设的，即动脉狭窄是由平滑肌细胞（SMC）表型改变引起的，响应于晚期胚胎发育期间机械环境的变化。拟议的研究还将通过改变动脉弹性或降低血压来改变目标发育期间的机械环境来确定动脉狭窄。该假设将进行检验 使用遗传改性的小鼠和药物治疗。将使用由不同蛋白质敲除弹性蛋白（ELN），fibulin-4（FBLN4）和赖氨酸氧化酶（LOX）引起的三种小鼠模型。弹性蛋白是弹性纤维的主要成分 动脉壁； Fibulin-4对于适当组装弹性纤维是必需的；赖氨酸氧化交联将弹性蛋白的可溶形式交联成其机械功能的形式。所有三个鼠标线 是围产期致死的，显示局部主动脉狭窄，但机械环境尚未表征。在晚期胚胎发育过程中打开或关闭的两种有条件的小鼠系也将用于确定改变动脉弹性是否最小化，防止或延迟变窄。最后，已建立的抗高血压药物将用于降低胚胎晚期发育期间的血压，并确定是否减少对SMC的血液动力学应力是否可最大程度地减少，预防或延迟动脉狭窄。在所有情况下，都将测量血压，血流和动脉机械性能来量化机械环境。超微结构研究和靶向基因阵列分析将决定机械环境如何影响细胞外基质（ECM）和SMC表型。这些研究对于识别导致动脉的机械和遗传途径很重要 在COA和SVA等疾病中狭窄，将测试预防性治疗。 公共卫生相关性：最常见的先天性血管缺陷是主动脉的缩合，如果未经治疗，其死亡率为75％到45岁。通常建议在5岁之前进行治疗，并且治疗并发症包括手术死亡率，重合和动脉瘤。拟议的研究的目的是检验以下假设：当机械环境发生变化时，血管细胞表型的变化引起的凝聚力是通过逆转机械环境中的变化来预防缩窄的。