Vascular Smooth Muscle Notch Signaling in Arterial Patterning and Function

项目总结/摘要 血管平滑肌细胞（VSMC）支持血管的形成、结构完整性和化学反应性， 这是发育、出生后成熟和血管系统功能所需的。根据处理 血管发生，其中内皮细胞（EC）合并形成原始的管状毛细血管网络， 血管平滑肌细胞的募集促进血管成熟或血管生成重塑， 信号和转录程序在内皮细胞和血管平滑肌细胞内的运作。这些活动的平衡 在生理和病理条件下严格调节血管形成和功能。 PI先前发表的研究表明，抑制体内VSMCs中的经典Notch信号传导， 导致不适当的脑动脉图案以及未能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， 提示Notch信号在动脉模式和侧支动脉形成中的重要作用。在 此外，这些解剖结构紊乱与脑血管疾病风险增加有关。 缺血性脑血管病和中风。综上所述，这些观察 支持我们的中心假设，即VSMC中的Notch信号提供了 动脉血管系统的正常组织和功能。 该提案的目标是进一步研究，在一个全面的方式，Notch信号在VSMC中的作用 体外和体内生物学。在目标1中，在携带Notch信号缺陷的VSMCs的小鼠胚胎中的研究 将着手绘制出生前发育过程中新生血管的时空组织图 作为观察到的出生后解剖异常的基础。目标2将解决的功能动力学 Notch信号缺陷的VSMCs在天然血管内通过检查血管反应性反应的生理 以及对大脑和外周血管稳态重要的化学刺激。最后，目标3将检查 通过离体和体外研究，部分改变了血管结构和VSMC功能的分子基础 评估Notch信号缺陷的VSMC的血管生成和血管重塑贡献。

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.