ELASTIN IN VESSEL DEVELOPMENT & VASCULAR DISEASES

描述(由申请人提供)：本次续展申请的目的将继续调查弹性蛋白沉积和组装的变化如何影响血管发育和心血管功能。我们还试图了解改变弹性纤维组装的弹性蛋白突变如何导致血管疾病。在之前的资助期间，我们显示了血压上升和发育期间弹性蛋白产生增加之间的强烈相关性。血压和弹性蛋白合成在胎儿和出生后期间协调增加，当弹性蛋白合成在P21-P30之间结束时，血压稳定。尽管对血流动力学和SMC基质产生的影响尚无普遍接受的解释，但壁应力被认为是主要因素。相比之下，ECM被视为对墙的力学性能有贡献的静态组件，但在其他方面对此事没有发言权。我们认为，随着心血管系统的成熟，弹性纤维形成过程中产生的过氧化氢作为信号分子直接影响细胞分化和心脏功能。我们的模型不同于传统的观点，即血压的变化完全通过与壁应力相关的信号直接产生基质，我们的模型认为，活性基质合成和成熟过程中产生的活性氧物种(ROS)信号通过直接信号或通过调节机械信号通路影响血压和细胞分化的调节。由于血压的升高只能在血管壁能够容纳的范围内发生，因此来自负责血管完整性的结构部件的反馈信号是向心血管系统发出信号的有效方式，表明管壁已经达到了所需的强度和适当的机械性能，以适应流量和压力的变化。将信号耦合到弹性蛋白的交联提供了有关弹性蛋白合成的信息，最重要的是，提供了关于弹性蛋白成熟状态的信息。因此，这一应用的基本假设是，弹性蛋白交联过程中产生的ROS提供了一种调节信号，影响了平滑肌细胞的分化和心血管生理学。我们还提出，弹性蛋白衍生的ROS影响血管紧张素信号通路，该通路与弹性蛋白不足时发生的适应性重构有关。我们的具体目标是：1)探索一种由弹性蛋白交联过程中产生的活性氧物种介导的新的信号机制。2)确定肾素-血管紧张素系统如何在妊娠晚期弹性蛋白不足时指导血管重塑。3)探讨挽救弹性蛋白功能不全(SVAS)的治疗策略。公共卫生相关性：该项目试图了解与影响血管发育和心血管功能的弹性蛋白基因突变相关的疾病背后的基本分子机制。

DESCRIPTION (provided by applicant): The aims of this renewal application will continue to investigate how changes in elastin deposition and assembly influence blood vessel development and cardiovascular function. We also seek to understand how elastin mutations that alter elastic fiber assembly lead to vascular disease. During the previous funding period we showed a strong correlation between the rise in blood pressure and the increase in elastin production during development. Blood pressure and elastin synthesis increase coordinately through the fetal and postnatal period and blood pressure stabilizes when elastin production ends between P21-P30. Although there is no generally accepted explanation for what directs the changes in hemodynamics and SMC matrix production, wall stress is considered to be the major player. The ECM, in contrast, is regarded as a static component that contributes to the mechanical properties of the wall but otherwise has no say in the matter. We propose that H2O2 generated during elastic fiber formation acts as a signaling molecule to directly influence cellular differentiation and cardiac function as the cardiovascular system matures. Instead of the traditional view that alterations in blood pressure direct matrix production exclusively through signals associated with wall stress, our model suggests that reactive oxygen species (ROS) signals generated during active matrix synthesis and maturation influence adjustments in blood pressure and cell differentiation through direct signaling or by modulating mechanical signaling pathways. Because increases in blood pressure can only occur to the extent that they can be accommodated by the vessel wall, feedback signals from the structural components responsible for vessel integrity are an efficient way to signal the cardiovascular system that the wall has achieved the required strength and appropriate mechanical properties to accommodate changes in flow and pressure. Coupling signaling to crosslinking of elastin provides information about both elastin synthesis and, most importantly, the maturation state of elastin. Thus, the underlying hypothesis of this application is that ROS generated during elastin crosslinking provide a regulatory signal that influences smooth muscle cell differentiation and cardiovascular physiology. We also propose that elastin-derived ROS influence the angiotensin signaling pathway and that this pathway is responsible for the adaptive remodeling that occurs in elastin insufficiency. Our specific aims are: 1) To explore a novel signaling mechanism mediated by reactive oxygen species generated during elastin crosslinking. 2) To determine how the renin-angiotensin system directs vascular remodeling in late gestation elastin insufficiency. 3) To explore treatment strategies designed to rescue elastin insufficiency (SVAS). PUBLIC HEALTH RELEVANCE: This project seeks to understand the basic molecular mechanisms behind diseases associated with mutations in the elastin gene that affect vascular development and cardiovascular function.