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

• 批准号: 7922565
• 负责人: AARON PROWELLER
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922565
• 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; angiogenesis; base; capillary; design; hemodynamics; in vivo; in vivo Model; mortality; myocardin; notch protein; novel; programs; public health relevance; response; vasculogenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Vascular smooth muscle cells (VSMCs) are required for the formation of a competent vascular system. Notch signaling is an important molecular pathway that regulates VSMC function and defects in Notch signaling are genetically linked to human vascular syndromes featuring stroke and congenital cardiovascular abnormalities. This proposal serves to identify at a mechanistic level the precise roles for Notch signaling in VSMCs that confer proper organization and function of the vasculature. The results from these investigations will provide the foundation for novel therapies for the treatment of vascular insufficiencies such as peripheral and cerebral arterial disease.

描述（由申请人提供）：血管平滑肌细胞（VSMCs）支持发育、出生后成熟和血管功能所需的形成、结构完整性和化学反应性。在血管发生过程中，内皮细胞（ECs）结合形成一个原始的管状毛细血管网络，VSMCs的募集促进血管成熟或血管生成重塑，这是由ECs和VSMCs内复杂的信号和转录程序相互作用所控制的。这些活动的平衡在生理和病理条件下对血管的形成和功能起着关键的调节作用。PI先前发表的研究表明，体内VSMCs中典型Notch信号的抑制导致脑动脉模式不正确以及无法形成成熟的动脉血管壁。这些发现确定了Notch信号在胜任血管形成中的vsmc自主作用，并暗示了Notch信号在动脉模式和侧支动脉形成中的重要作用。此外，这些解剖紊乱与诱导缺血小鼠脑血管功能不全和中风的风险增加有关。综上所述，这些观察结果支持了我们的中心假设，即VSMCs中的Notch信号提供了动脉血管系统正常组织和功能所需的指导性线索。本课题旨在进一步全面研究Notch信号在体外和体内VSMC生物学中的作用。在Aim 1中，将对含有Notch信号缺陷VSMCs的小鼠胚胎进行研究，以绘制出出生前发育过程中新生血管的时空组织，作为观察到的出生后解剖异常的基础。目的2将通过检查对大脑和外周血管稳态重要的生理和化学刺激的血管反应来解决天然血管中Notch信号缺陷的VSMCs的功能动力学。最后，Aim 3将通过评估Notch信号缺陷VSMC血管生成和血管重塑的离体和体外研究，部分检查血管结构和VSMC功能改变的分子基础。公共卫生相关性：血管平滑肌细胞（VSMCs）是形成有能力的血管系统所必需的。Notch信号是调控VSMC功能的重要分子通路，Notch信号缺陷与人类血管综合征（包括中风和先天性心血管异常）存在遗传关联。该建议有助于在机制水平上确定Notch信号在VSMCs中赋予血管系统适当组织和功能的精确作用。这些研究结果将为治疗血管功能不全（如外周和脑动脉疾病）的新疗法提供基础。