ELASTIN IN VESSEL DEVELOPMENT & VASCULAR DISEASES

描述（由申请人提供）：本次续期申请的目的是继续研究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。在之前的融资期间，我们发现在开发过程中血压升高和弹性蛋白产量增加之间存在很强的相关性。血压和弹性蛋白合成在胎儿期和产后协调增加，当弹性蛋白在P21-P30之间结束时血压稳定。虽然没有普遍接受的解释是什么导致了血流动力学和SMC基质产生的变化，但壁应力被认为是主要因素。相比之下，ECM被认为是一个静态组件，有助于壁面的机械性能，但在其他方面没有发言权。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H2O2作为一种信号分子直接影响细胞分化和心脏功能。传统观点认为，血压的改变完全通过与壁应力相关的信号直接影响基质的产生，而我们的模型表明，在主动基质合成和成熟过程中产生的活性氧（ROS）信号通过直接信号传导或调节机械信号传导途径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可以容纳的范围内发生，因此负责血管完整性的结构部件的反馈信号是一种有效的方式，可以向心血管系统发出信号，表明血管壁已达到所需的强度和适当的机械性能，以适应流量和压力的变化。耦合信号到弹性蛋白交联提供了关于弹性蛋白合成的信息，最重要的是，提供了弹性蛋白成熟状态的信息。因此，该应用的潜在假设是弹性蛋白交联过程中产生的ROS提供了影响平滑肌细胞分化和心血管生理的调节信号。我们还提出弹性蛋白衍生的活性氧影响血管紧张素信号通路，该通路负责弹性蛋白不足时发生的适应性重构。我们的具体目标是：1)探索弹性蛋白交联过程中活性氧介导的新信号机制。2)确定肾素-血管紧张素系统如何指导妊娠晚期弹性蛋白不足的血管重构。3)探讨弹性蛋白功能不全（SVAS）的救治策略。公共卫生相关性：该项目旨在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.