Flow regulation of the Alk1/Eng pathway in vascular homeostasis and disease

项目摘要 流体切应力依赖性血管重构是胚胎发育的重要调控机制 在发育和成人血管稳态中，它优化了流向靶组织的血流。相反，联合国- 或失调的重塑导致血管畸形，而不良重塑是血液流变学的一个关键方面， 冠状动脉和外周动脉疾病中的血流限制。我们的初步数据显示， 具有两个相互抑制状态的网络，一个与血管稳定性相关，另一个与生理性相关。 向外重塑或病理性AVM形成。这些结果使我们能够提出一个统一的假设， 连接生理和病理重塑，并建议存在控制点，可以 操纵以增加或减小血管腔直径。该项目旨在阐明这些 调节机制，然后利用这些新的见解来研究它们与血管 开发，以确定患有过度病理性重塑的HHT患者的治疗靶点， 并确定冠状动脉和外周动脉疾病患者的治疗靶点， 重塑受损。我们将定义这种新型EC剪切应力机制的分子基础，确定 它的生物学作用，并开发和测试基于这一知识的治疗应用。

PROJECT SUMMARY Fluid shear stress-dependent vessel remodeling is an essential regulatory mechanism in embryonic development and in adult vascular homeostasis where it optimizes blood flow to target tissues. Conversely, un- or mis-regulated remodeling results in vascular malformations, while poor remodeling is a key aspect of blood flow restriction in coronary and periphery artery disease. Our preliminary data reveal the existence of a regulatory network with two mutually inhibitory states, one associated with vessel stability and one with physiological outward remodeling or pathological AVM formation. These results allow us to propose a unifying hypothesis that links physiological and pathological remodeling, and suggest the existence of control points that can be manipulated to either increase or decrease vascular lumen diameter. The project aims to elucidate these regulatory mechanisms and then harness these new insights to investigate their relevance to vascular development, to identify therapeutic targets for HHT patients who suffer from excessive pathological remodeling, and identify therapeutic targets for coronary and peripheral artery disease patients where physiological remodeling is impaired. We will define the molecular basis of this novel EC shear stress mechanism, determine its biological role and develop and test therapeutic applications based on this knowledge.