Vascular Smooth Muscle Notch Signaling in Arterial Patterning and Function

项目摘要/摘要 血管平滑肌细胞(VSMCs)支持血管的形成、结构完整性和化学响应性 是血管系统发育、出生后成熟和功能所必需的。遵循这个过程 其中内皮细胞(ECs)结合形成原始的管状毛细血管网络， VSMCs的募集通过复杂的相互作用促进血管成熟或血管新生重塑 在ECs和VSMC内运行的信号和转录程序。这些活动的平衡 在生理和病理条件下关键地调节血管的形成和功能。 PI之前发表的研究表明，体内VSMCs中规范的Notch信号的抑制 导致不正确的脑动脉构型以及未能形成成熟的动脉血管壁。这些 研究结果表明，VSMC-自主的Notch信号在合格血管的形成和形成中发挥作用 提示Notch信号在动脉构型和侧支动脉形成中起重要作用。在……里面 此外，这些解剖结构的紊乱与脑血管风险的增加有关。 诱发小鼠脑缺血后的功能不全和卒中。总而言之，这些观察结果 支持我们的中心假设，即VSMC中的Notch信号提供了所需的指导性线索 动脉血管系统的适当组织和功能。 这项建议的目的是进一步全面研究Notch信号在VSMC中的作用 生物学在体外和体内。在目标1中，对含有Notch信号缺陷的VSMC的小鼠胚胎的研究 将对新生血管在出生前发育期间的时空组织进行测绘 作为观察到的产后解剖异常的基础。目标2将解决功能动力学问题 通过检测生理性血管反应性反应来阻断天然血管内信号转导缺陷的VSMCs 以及对大脑和外周血管动态平衡很重要的化学刺激。最后，《目标3》将考察 通过体外和体外研究部分改变血管结构和VSMC功能的分子基础 评估Notch信号缺陷的VSMCs对血管生成和血管重塑的贡献。

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.