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Vascular Smooth Muscle Notch Signaling in Arterial Patterning and Function

动脉模式和功能中的血管平滑肌切迹信号传导

基本信息

批准号：
8467028
负责人：
AARON PROWELLER
金额：
$ 36.99万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467028
关键词：
Address Adult Animals Arteries Biological Models Blood Blood Vessels Blood capillaries Blood flow Cardiovascular Abnormalities Cell physiology Cellular biology Cerebral Arterial Diseases Cerebrovascular Insufficiency Cerebrum Chemicals Complex Cues Defect Deformity Development Embryo Endothelial Cells Equilibrium Evolution Failure Foundations Functional disorder Gene Expression Genetically Engineered Mouse Goals Growth Factor Homeostasis Human Image In Vitro Investigation Ischemia Link Maintenance Maps Mediating Molecular Morphogenesis Mus Pathologic Pathway interactions Pattern Peripheral Peripheral arterial disease Physiological Predisposition Process Publishing Resolution Risk Role Signal Transduction Smooth Muscle Myocytes Stimulus Stress Stroke Structure Syndrome Tubular formation United States Vascular Endothelial Cell Vascular Smooth Muscle Vascular System abstracting angiogenesis base capillary design hemodynamics in vivo in vivo Model mortality myocardin notch protein novel programs public health relevance response vasculogenesis

项目摘要

Project Summary/Abstract Vascular smooth muscle cells (VSMCs) support the formation, structural integrity and chemical responsivity required for development, post-natal maturation and function of the blood vasculature. Following the process of vasculogenesis wherein endothelial cells (ECs) coalesce to form a primitive, tubular capillary network, recruitment of VSMCs promotes vessel maturation or angiogenic remodeling governed by a complex interplay of signaling and transcriptional programs operating within ECs and VSMCs. The balance of these activities critically regulates vascular formation and function under physiologic and pathologic conditions. Previous studies published by the PI revealed that suppression of canonical Notch signaling in VSMCs in vivo resulted in improper cerebral arterial patterning as well as failure to form mature arterial vessel walls. These findings identified a VSMC-autonomous role for Notch signaling in the formation of competent vessels and implicated an important role for Notch signaling in arterial patterning and collateral artery formation. In addition, these anatomical derangements were associated with an increased risk for cerebrovascular insufficiency and stroke in mice subjected to induced ischemia. Taken together, these observations support our central hypothesis that Notch signaling in VSMCs provides instructive cues required for proper organization and function of the arterial vasculature. The goal of this proposal is to further study, in a comprehensive manner, the role of Notch signaling in VSMC biology in vitro and in vivo. In Aim 1, studies in mouse embryos harboring Notch signaling-deficient VSMCs will be undertaken to map the temporal-spatial organization of emerging vessels during pre-natal development as a basis for the observed post-natal anatomical abnormalities. Aim 2 will address the functional dynamics of Notch signaling-deficient VSMCs within native vessels by examining vasoreactive responses to physiological and chemical stimuli important for cerebral and peripheral vascular homeostasis. Finally, Aim 3 will examine the molecular basis for altered vessel structure and VSMC function in part through ex vivo and in vitro studies assessing the angiogenic and vessel remodeling contributions of Notch signaling-deficient VSMCs.

项目概要/摘要血管平滑肌细胞 (VSMC) 支持形成、结构完整性和化学反应性发育、产后成熟和血管功能所需。遵循流程血管生成，其中内皮细胞（EC）结合形成原始的管状毛细血管网络， VSMC 的募集促进血管成熟或血管生成重塑，受复杂的相互作用控制 EC 和 VSMC 内运行的信号传导和转录程序。这些活动的平衡在生理和病理条件下关键调节血管形成和功能。 PI 之前发表的研究表明，抑制体内 VSMC 中的经典 Notch 信号传导导致脑动脉模式不正确以及无法形成成熟的动脉血管壁。这些研究结果确定了 Notch 信号在主管血管形成中的 VSMC 自主作用，暗示Notch信号在动脉模式和侧支动脉形成中发挥重要作用。在此外，这些解剖结构紊乱与脑血管病风险增加有关诱发缺血的小鼠中的功能不全和中风。综合起来，这些观察支持我们的中心假设，即 VSMC 中的 Notch 信号传导提供了所需的指导性线索动脉脉管系统的适当组织和功能。本提案的目的是进一步全面研究Notch信号在VSMC中的作用体外和体内生物学。在目标 1 中，对含有 Notch 信号传导缺陷的 VSMC 的小鼠胚胎进行研究将绘制产前发育期间新兴血管的时空组织图作为观察到的产后解剖异常的基础。目标 2 将解决功能动态问题通过检查对生理的血管反应反应来切开天然血管内信号缺陷的 VSMC 和化学刺激对于脑和外周血管稳态很重要。最后，目标 3 将检查部分通过离体和体外研究改变血管结构和 VSMC 功能的分子基础评估Notch信号传导缺陷的VSMC对血管生成和血管重塑的贡献。