Elastin deposition and stenosis formation in the developing aorta

发育中的主动脉中的弹性蛋白沉积和狭窄形成

• 批准号: 10266226
• 负责人: Jessica Wagenseil
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266226
• 关键词: Address; Adolescence; Adolescent; Adult; Aorta; Aortic Valve Stenosis; Arteries; Biophysical Process; Biophysics; Blood Pressure; Cardiac; Cardiovascular Physiology; Cell Proliferation; Cells; Child; Collagen; Complex; Complex Mixtures; Computer Models; DNA Sequence Alteration; Deposition; Development; Disease; Elasticity; Elastin; Embryo; Experimental Models; Gene Expression; Genes; Geometry; Goals; Growth; Half-Life; Investigation; Laws; Lead; Location; LoxP-flanked allele; Mathematics; Measures; Mechanics; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutation; Myoblasts; Operative Surgical Procedures; Organ; Process; Proteins; Repeat Surgery; Smooth Muscle Myocytes; Stenosis; Stress; Structure; Supravalvular aortic stenosis; Therapeutic; Time; Translating; Variant; Vascular Diseases; Workload; base; cell motility; cell type; cellular targeting; critical developmental period; heart function; human disease; insight; mechanical behavior; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; predictive modeling; prevent; public health relevance; sudden cardiac death; theories; young adult

ABSTRACT Elastin is a fundamental component of large arteries, providing elasticity to reduce cardiac workload and protect downstream organs. Elastin is expressed only during a narrow timeframe initiating in the late embryonic stage and ending in adolescence. This short expression window is possible due to elastin’s 70-year half-life and makes correct deposition of elastin in the developmental period critically important. Elastin is deposited predominantly by smooth muscle cells (SMCs) in concentric layers called elastic laminae. There is a complex mixture of SMCs from different embryonic origins and differentiation states within the ascending aortic wall, yet how these different mural cell types contribute to elastic laminae formation is unknown. Congenital mutations in the elastin gene lead to elastin insufficiency and cause supravalvular aortic stenosis (SVAS). There are no therapeutic strategies to increase elastin levels in SVAS and preventative surgery to alleviate aortic stenosis is the primary treatment to avoid sudden cardiac death. While surgery has good early results, there is a significant need for reoperation, especially in children. The mechanisms by which reduced elastin causes aortic stenosis are not well understood. Previous mouse models have advanced our understanding of SVAS, but new mouse models with more precise control of the location and timing of elastin deposition during development are needed to refine debated mechanisms. Currently proposed biophysical mechanisms relate changes in aortic elasticity, growth, cellular proliferation, and/or collagen deposition to stenosis formation. A computational model of aortic growth and remodeling (G&R) would be useful to evaluate the physical plausibility and limitations of competing mechanisms. Computational G&R models have provided insight into processes of aortic remodeling in adult vascular disease, but have seen limited application for processes of normal and abnormal aortic development in congenital disease. The overall goal of this proposal is to better understand the process of elastin deposition in normal ascending aortic development and how reduced elastin levels lead to stenosis in abnormal aortic development. Three specific aims are proposed to accomplish this goal: Aim 1. Determine how different cell types within the aortic wall contribute to elastic laminae formation; Aim 2. Quantify the effects of graded elastin amounts on aortic structure and cardiovascular function; and Aim 3. Utilize a computational model to describe and predict how variations in elastin amount and transmural organization lead to aortic stenosis through stress-mediated G&R. A new elastin-floxed mouse that allows elastin expression to be reduced in a cell type and time point specific manner when bred to Cre expressing lines will be used for Aims 1 and 2. A computational model based on laws of nonlinear elasticity, continuum mechanics, and stress- mediated growth and matrix deposition will be used for Aim 3. Model predictions in Aim 3 will be compared to experimental results for normal and abnormal aortic development in Aims 1 and 2. Successful completion of these aims may lead to novel strategies to treat elastin insufficiency and/or aortic stenosis in SVAS.

摘要